KR20080022539A - 키메라 단백질 - Google Patents
키메라 단백질 Download PDFInfo
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- KR20080022539A KR20080022539A KR1020077008321A KR20077008321A KR20080022539A KR 20080022539 A KR20080022539 A KR 20080022539A KR 1020077008321 A KR1020077008321 A KR 1020077008321A KR 20077008321 A KR20077008321 A KR 20077008321A KR 20080022539 A KR20080022539 A KR 20080022539A
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Abstract
본 발명은 융합 단백질의 아미노 말단에 위치하고 제1사이토카인 또는 성장인자와 특이적으로 결합하여 중화시키는 제1구역; 및 융합 단백질의 카복실 말단에 위치하고 IL-1 수용체가 풍부한 염증부위와 같은 질병부위에 종종 풍부한 제2사이토카인 수용체와 특이적으로 결합하는 제2구역을 포함하는 융합 단백질에 관한 것이다. 또한, 상기 제2구역은 보통 IL-1 수용체 길항제 및 이와 기능상 동등한 유사물들과 같은 수용체 길항제이다. 핵산을 가지는 융합 단백질, 벡터들 및 숙주세포를 암호화하는 핵산들, 및 관련 조성물 및 염증성 질병 및 염증과 공존하는 징후들을 목표로 하는 방법도 기재되어있다.
융합 단백질, 중화, 염증
Description
본 발명은 전체 내용이 본 명세서에 참증으로서 인용된 2004년 10월 12일에 출원된 미국 가출원 제60/618,476; 2004년 11월 17일에 출원된 미국 가출원 제60/628,994; 및 2005년 2월 1일에 출원된 미국 가출원 "혈관생성을 목표로 하는 융합 단백질로서의 IL-1ra"에 의한 우선권을 가진다.
본 발명은 염증, 천식 및 암과 같은 다양한 질병들의 치료에 유용한 키메라 단백질 치료용 제제에 관한 것이다.
염증은 기계적 손상, 감염 또는 항체 자극에 의해 발생되는 것과 같은 상해에 대한 신체의 보호반응이다. 염증반응은 염증이 자가항원과 같은 부적절한 자극에 의해 유발될 때 병리학적으로 나타나며, 강조된 형태로 표현되거나 또는 해로운 제제가 제거된 한참 뒤까지 지속된다. 수많은 치료용 단백질이 염증반응 억제, 염증관련 천식의 치료, 및 병리학적 혈관생성의 감소를 위해 발전해왔다. 그러나,이들 중 많은 것들이 부족한 효능, 부작용들 또는 불안정 때문에 만족스럽지 못하다.
본 발명은 생활성(bioactive) 또는 치료용 단백질들에 대한 융합파트너로서 IL-1 수용체 길항제(IL-1ra)의 용도 또는 동등한 그 기능에 관한 것이다. 생활성 또는 치료용 단백질들의 예로는 종양괴사인자(TNF) 중화제들, IL-18 중화제들, IL-4/IL-13 중화제들, VGEF 중화제, 안지오포이에틴(angiopoietin) 중화제, 및 기타 염증성 천식 및 혈관생성 관련 징조의 치료에 유용한 것들이 포함된다.
본 발명의 일태양은 융합단백질의 아미노 말단에 위치하여 제1사이토카인(cytokine) 또는 성장인자와 특이적으로 결합하는 제1구역; 및 융합단백질의 카복시 말단에 위치하여 제2사이토카인의 수용체 또는 성장인자, 즉 염증부위에 풍부한 IL-1 수용체와 특이적으로 결합하는 제2구역을 포함하는 융합단백질을 특징으로 하고있다. 영역들은 수술가능하게 연결되어 있고, 제1 및 제2사이토카인은 염증부위에 풍부하다.
앞서 언급한 융합단백질은 당화(glycosylate)될 수 있다. 이것은 제1구역 및 제2구역을 결합하는 연결구역을 더욱 포함한다. 연결구역은 이합체화의 기능이 있다. 일 실시예에서, 연결구역은 면역글로불린의 Fc분절 또는 이와 기능상 동등한 것을 포함한다. 바람직하게는 면역글로불린은 IgA, IgE, IgD, IgG 또는 IgM이다. 더욱 바람직하게는 면역글로불린은 IgG 또는 이것의 Fc분절, 즉, SEQ ID NO.:2이다. 면역글로불린사슬은 SEQ ID NO.:9, 11, 12, 23 또는 24; 또는 이들과 기능상 동등한 것을 포함한다.
앞서 언급한 융합단백질에서, 제1구역은 VEGF, Ang, TNF, IL18, IL4 또는 IL6, 또는 이들과 기능상 동등한 것에 결합하고 중화할 수 있다. 예를 들면, 제1구역은 VEGF, 안지오포이틴, TNF, IL18, IL4 , IL13 또는 IgE; 또는 이들과 기능상 동등한 것들에 특이적으로 결합하여 중화하는 면역글로불린의 사슬의 시퀀스를 포함할 수 있다. 제1구역은 또한 VEGF, Ang, TNF, IL18, IL4 , IL13 또는 IgE, 즉, SEQ ID NO.:3, 6, 15 또는 19의 수용체의 시퀀스를 포함할 수 있다.
앞서 언급한 융합단백질에서, 제2구역은 IL-1의 수용체에 특이적으로 결합할 수 있다. 제2구역은 IL-1ra(SEQ ID NO.:1)의 시퀀스 또는 이와 기능상 동등한 것을 포함하는 구역과 같은 IL-1의 길항제가 될 수 있는 구역이다. 이에 따라, 전술한 융합단백질은 SEQ ID NO.:5, 8, 10 ,13, 17, 18, 21, 22, 24 또는 25를 포함할 수 있다.
본 발명의 또다른 태양은 전술한 융합 단백질을 암호화(encode)하는 시퀀스를 포함하는 분리된 핵산을 특징으로 하고 있다. 이는 SEQ ID NO: 1-25중 하나를 암호화하는 시퀀스를 포함할 수 있다.
본 발명의 범위 내에서, 조성물은 (i)전술한 융합 단백질 또는 이를 암호화하는 핵산 및 (ii)약학적으로 수용가능한 담체를 포함하고 있다. 또한 본 발명의 범위 내에서, 본 발명은 대상 내의 면역반응을 조절하는 방법이다. 이 방법은 과도한 염증반응, 면역반응, 및 혈관생성반응으로 특징지어지는 질환을 가지거나 이러한 질환이 발생할 위험이 있는 대상을 확인하는 단계; 및 전술한 융합단백질 또는 융합단백질을 암호화하는 핵산의 유효량을 상기 대상에게 투여하는 단계를 포함한다. 상기 대상은 동종 또는 이종 이식을 받았거나 받기로 고려되는 것이 될 수 있다. 상기 질환의 예는 염증성 질병, 자가면역 질병, 알레르기성 질병, 또는 암을 포함한다. 상기 질환이 혈관생성의존성인 암인 경우, SEQ ID NO: 24를 포함하는 융합 단백질이 바람직하다.
다른 태양에서, 본 발명은 대상 내에서 유전자 재조합 단백질의 반감기를 증가시키는 방법을 특징으로 하고 있다. 본 방법은 융합 단백질 키메라를 형성하기 위해 유전자 재조합 단백질을 SEQ ID NO: 1을 포함하는 구역 또는 이와 기능상 동등한 것과 결합하는 단계: 및 대상 내에서의 융합 단백질의 반감기를 측정하는 단계를 포함한다. 유전자 재조합 단백질은 사이토카인이나 성장인자와 결합한다.
본 발명은 또한 대상 내에서의 유전자 재조합 단백질의 효능을 증가시키는 방법을 특징으로 하고 있다.본 방법은 융합 단백질 키메라를 형성하기 위해 유전자 재조합 단백질을 SEQ ID NO: 1을 포함하는 구역 또는 이와 기능상 동등한 것과 결합하는 단계: 및 대상 내에서의 융합 단백질의 효능을 측정하는 단계를 포함한다. 일 실시예에서, 융합 단백질 키메라는 염증부위 또는 대상 내의 IL-1 수용체가 풍부한 질병 부위의 IL-1 수용체 및 사이토카인 또는 성장인자 모두에 결합하여 동시에 중화한다. 다른 양태에서, 상기 융합 단백질 키메라는 염증부위 또는 대상 내의 IL-1 수용체가 풍부한 질병 부위의 IL-1 수용체 및 사이토카인 또는 성장인자 모두의 활성을 중화하거나 이에 대항한다.
또 다른 태양에서, 본 발명은 치료 단백질을 대상 내의 목적 부위에 운반하는 방법을 특징으로 하고 있으며, 상기 방법은 융합 단백질 키메라를 형성하기 위해 치료 단백질을 SEQ ID NO: 1을 포함하는 구역 또는 이와 기능상 동등한 것과 결합시키는 단계; 및 필요로 하는 대상에 융합 단백질 키메라를 투여하는 단계를 포함한다. 치료 단백질은 IL-1 수용체에 풍부한 염증 부위을 목표로 한다. 일 실시예에서, SEQ ID NO: 1을 포함하는 구역 또는 이와 기능상 동등한 것은 IL-1 수용체에 결합하며, 유전자 재조합 단백질은 사이토카인 또는 성장인자에 결합하여 중화시키는 치료 단백질이다.
분리된 폴리펩타이드는 근본적으로 결합된 분자들로부터 실질적으로 자유로운 폴리펩타이드를 말하는 것으로, 즉, 적어도 건조 중량의 75%(즉, 75% 내지 100% 사이의 어떠한 수 포함)순수하다. 순도는 어떠한 적절한 표준방법, 예를 들면 컬럼 크포마토그래피, 폴리아크릴아마이드 겔 전기영동, 또는 HPLC에 의해 측정될 수 있다. 본 발명의 분리된 폴리펩타이드는 천연자원(자연상태 타입의 폴리펩타이드류)으로부터 정제, 유전자 재조합 DNA 기술 또는 화학적 방법에 의해 제조될 수 있다.
핵산은 DNA 분자(즉, cDNA 또는 게놈 DNA), RNA 분자(즉, mRNA), 또는 DNA 또는 RNA 유사물을 가리킨다. DNA 또는 RNA 유사물은 뉴클레오티드(nucleotide) 유사물들로부터 합성될 수 있다. 핵산 분자는 단일가닥 또는 이중가닥이 될 수 있으나, 바람직하게는 이중가닥 DNA이다. "분리된 핵산"은 그 구조가 자연적으로 발생하는 어떠한 핵산 또는 자연적으로 발생하는 게놈 핵산의 어떠한 분절과 동일한 핵산을 말한다. 따라서 이 용어는 예를 들면, (a)자연적으로 발생하는 게놈 DNA 분자의 부분의 시퀀스를 가지지만 그 내부에서 자연적으로 발생시키는 유기체의 게놈 내의 분자의 상기 부분에 인접한 암호화 시퀀스에 의해 인접되지 않는 DNA; (b)결과분자가 자연적으로 발생한 어떠한 벡터 또는 게놈 DNA와 동일하지 않은 방식으로 진핵동물 또는 원핵동물의 벡터 또는 게놈 DNA에 주입되는 핵산; (c)cDNA, 게놈분절, 폴리머라아제 체인반응(PCR)에 의해 제조된 분절, 또는 제한절편과 같은 고립분자; 및 (d)잡종유전자, 즉, 융합 단백질을 암호화하는 유전자의 일부인 유전자 재조합 뉴클레오티드 시퀀스를 포함한다.
전술한 핵산은 본 발명의 폴리펩타이드를 발현시킬 수 있다. 이러한 목적으로, 발현벡터를 생성시키기 위해 핵산을 적절한 조절서열(regulatory sequence)에 수술적으려 연결시킬 수 있다.
벡터는 자신에 연결된 다른 핵산을 운반할 수 있는 핵산 분자를 가리킨다. 벡터는 자동복제(autonomous replication)의 기능이 있을 수 있거나 숙주 DNA 내로 통합될 수 있다. 벡터의 예로는 플라스미드, 코스미드 또는 바이러스 벡터가 포함된다. 벡터는 숙주세포 내에서의 핵산 발현에 적절한 형태인 핵산을 포함한다. 바람직하게는 벡터는 발현되도록 핵산에 수술적으로 연결된 하나 이상의 조절서열을 포함한다. "조절서열"은 프로모터, 인핸서(enhancer), 및 기타 발현 조절 성분들(예를 들면, 아데닐중합체 형성 시그널)을 포함한다. 조절서열은 뉴클레오티드 시퀀스의 구조적 발현을 이끄는 것들뿐만 아니라, 조직-특이적인 조절 및/또는 유발가능 시퀀스를 포함한다. 발현벡터의 설계는 이송될 숙주세포의 선택, 원하는 단백질 또는 RNA의 발현 정도, 및 이와 유사한 것들과 같은 요인에 의존할 수 있다. 발현벡터는 본 발명의 폴리펩타이드를 제조하기 위해 숙주세포 내로 도입될 수 있다. 또한 본 발명의 범위 내에서, 숙주세포는 전술한 핵산을 포함한다. 그 예로는 대장균(E. coli)세포들, 곤충세포들(예를 들면, 바큘로바이러스(baculovirus) 발현벡터들), 효모세포들, 또는 포유류세포들이 포함된다. 괴델(Goeddel), 1990, 유전자발현 기술(Gene Expression Technology: Methods in Enzymology 185, 아카데믹 출판사, 샌디에이고, 캘리포니아)을 참조할 수 있다. 본 발명의 폴리펩타이드를 제조하기 위해, 본 발명의 핵산에 의해 암호화되는 폴리펩타이드의 발현을 용인하는 조건 하에 배지 내에서 숙주세포를 배양할 수 있고, 배양된 세포 또는 세포의 배지로부터 폴리펩타이드를 정제할 수 있다. 선택적으로는, 본 발명의 핵산은 체외에서 예를 들면, T7 프로모터 조절 시퀀스 및 T7 폴리머라아제를 이용하여 전사 또는 번역될 수 있다.
단백질 인자의 "기능상 동등한 것"은 단백질의 폴리펩타이드 유도체, 예를 들면 하나 이상의 돌연변이 지점, 삽입, 결손, 절단, 융합 단백질, 또는 이들의 유전자 재조합을 가지는 단백질을 가리킨다. 이것은 인자의 활성, 예를 들면 사이토카인, 성장인자, 또는 이들의 수용체에의 결합능력을 실질적으로 보유한다.
본 발명의 하나 이상의 자세한 실시예들이 아래의 상세한 설명에 기재되어있다. 본 발명의 다른 특징, 목적, 및 장점들은 상세한 설명 및 청구항들로부터 명백할 것이다.
본 발명은 적어도 부분적으로는 IL-1ra 또는 이와 기능상 동등한 것이 융합 파트너로서 수많은 생활성(bioactive) 단백질들, 예를 들면, 항 염증 단백질들, 항 천식 단백질들, 및 항 혈관형성 단백질들의 생화학적 수명 및 효능을 연장시킨다는 발견에 기초하고 있다. 이러한 단백질들의 예로는 종양괴사인자(TNF) 중화제들, IL-18 중화제들, IL-4/IL-13 중화제들, VEGF 중화제, 안지오포이에틴 중화제들이 포함된다.
생활성 단백질에 대한 N-말단의 단백질 융합은 종종 구체적으로는 거대 단백질 융합 파트너들에 대한 완벽한 활성 손실을 야기시킨다. 예를 들면, 효소전구체(酵素前驅體) 및 호르몬전구체들은 이들의 N-말단에서의 프로펩타이드 융합 때문에 활성이 없다. 이러한 전(pro)-분해 효소들 및 호르몬전구체들은 이들의 프로펩타이드들이 떨어져나갈때 까지만 생화학적으로 활성을 가지게 된다. 또한, 거대 단백질의 융합은 낮은 발현수율을 야기시킨다. 예상치못하게도, IL-1ra 융합된 단백질들은 포유류 숙주세포들 내에서 상업적으로 생산될 수 있다. 융합은 활성 IL-1ra의 IL-1수용체 결합 및 중화 작용, 또는 이들이 융합된 생활성 단백질의 결합 및 중화작용을 방해하지 않는다. 또한 예상치못하게도, IL-1ra(예를 들면 포유동물이 당화시킨) 또는 이와 기능상 동등한 것은 생활성 단백질들의 생화학적 수명을 연장시킬 뿐만 아니라 이들을 IL-1 수용체가 풍부한 염증 부위로 이끈다.
IL
-1
ra
IL-1은 대식세포(macrophage)/단핵구 혈통의 세포들에 의해 생산된 사이토카인이다. 이것은 두가지 형태로 생산된다: IL-1 알파 및 IL-1 베타. IL-1 단백질은 특정 IL-1 수용체(IL-1R)에 결합함으로써 세포들에 대한 생화학적 효능을 개시한다. IL-1R은 일반적으로 IL-1 반응성 세포들의 형질막 상에 발현된다.
IL-1 수용체 길항제(IL-1ra)는 IL-1의 중성 억제제로 작용하는 인간 단백질이다. IL-1ra는 IL-1에 의해 야기된 생화학적 활성을 억제하는데 사용되어왔다. 이것은 세포막 결합 IL-1 수용체들에 결합하여 IL-1이 동일한 IL-1 수용체들에 결합하는 것을 방지한다. IL-1 수용체는 대부분 염증부위들(Deleuran 등, 1992; Laken VD 등, 1997) 및 림프구들(lymphocyes)(Dowel SK 등, 1990)에 발현된다. 따라서, IL-1ra는 이들에 융합된 치료 단백질(예를 들면, 후술할 TNF 중화제)을 IL-1 수용체가 풍부한 염증 부위에 이끌 수 있다. 이러한 지향효과 때문에 치료단백질의 감소된 유효 복용량이 필요하고, 따라서 부작용을 감소시키거나 효능을 향상시킨다. 더욱이, IL-1ra 및 융합 파트너 사이의 협동은 두 단백질들 각각 또는 적어도 부분적으로는 동일한 위치에 가는 융합 단백질에 의한 조합의 경우보다 증대된 치료효과를 이끌어낸다.
IL-1ra 및 이와 기능상 동등한 것은 본 발명을 실시하는데 사용될 수 있다. IL-1ra와 기능상 동등한 것은 전술한 바와 같이 IL-1ra의 폴리펩타이드 유도체(SEQ ID NO: 1)를 가리킨다. 이는 실질적으로 IL-1ra의 활성을 가지는데, 즉, 예를 들면 IL-1 수용체에 결합하여 IL-1이 동일한 IL-1 수용체들에 결합하는 것을 방지한다. IL-1ra 및 이와 기능상 동등한 것은 적어도 하나의 인터류킨-1 수용체 길항제 영역을 포함하는데, 이는 IL-1 수용체 계열의 구성원들에 특이적으로 결합하여 세포성 수용체들의 IL-1 및 이들 계열의 구성원들에 대한 활성을 방지하는 기능을 하는 영역을 가리킨다. IL-1 수용체 계열은 몇몇 수용체 구성원들을 포함한다. 이에 따라, 몇개의 상이한 IL-1 계열 길항제들 및 작용제들이 있다. 이러한 IL-1 길항제들은 동일한 IL-1 수용체 계열의 구성원들에 필수적으로 결합하지 않을 수 있다. 이러한 IL-1ra는 IL-수용체 계열의 구성원들에 결합하거나 및/또는 IL-1 계열 구성원들의 활성을 중화하는 모든 IL-1 길항제들을 나타내는데 사용된다.
IL-1ra와 기능상 동등한 것은 인터류킨-1 수용체 길항제 영역을 포함한다. 이 영역은 IL-1 수용체 계열의 구성원들에 특이적으로 결합하여 IL-1 및 이들 계열의 구성원들에 대한 세포성 수용체들의 활성을 방지하는 기능이 있는 영역을 가리킨다. 인터류킨-1 수용체 길항제의 예로는 IL-1ra(미국 특허 제6,096,728), IL-1 HY1 또는 IL-1계열 구성원 5(미국 특허 제6,541,623), IL-1HY2 또는 IL-1 계열 구성원 10(미국 특허 제6,365,726), IL-1ra 베타(미국 6,399,573), 기타 IL-1 길항제 구성원들 및 이들과 기능상 동등한 것들, 즉, IL-1ra로부터 유도된 폴리펩타이드들, 예를 들면 하나 이상의 돌연변이, 삽입, 손실, 절단 또는 이들의 조합 지점을 가지는 단백질이 포함된다. 이들은 실질적으로 IL-1 수용체에 특이적으로 결합하여 IL-1에 대한 세포성 수용체들의 활성을 방지하는 작용을 보유한다. 이들은 SEQ ID NO: 1 또는 SEQ ID NO: 1의 분절을 포함할 수 있다. 바람직하게는, IL-1ra는 당화된 포유류 폴레펩타이드이다. 인터류킨-1 수용체 길항제의 작용은 D10 의존성 IL-1을 사용한 세포에 기초한 IL-1 중화 분석법(실시예 3 참조), 및 기타 IL-1 계열 구성원 중화 분석법을 통해 측정될 수 있다.
바람직하게는, IL-1ra 또는 이와 기능상 동등한 것은 당화된 폴리펩타이드이다. 천연의 IL-1ra는 두가지의 N-결합 당화 부위로 당화된다(미국 특허 제6,096,728). 이들 두가지의 N-결합 당화부위들은 IL-1ra의 체내 활성, 구체적으로는 이들의 생화학적 수명, 및 이들의 혈청 단백질 결합특성에 중요하다. 대장균 생성 IL-1ra인 키네레트(Kineret)는 사후 번역 변화가 부족하다. 그 결과, 인간 혈청 단백질에 현저하게 결합하는 경향이 있고, 낮은 체내 효능을 가진다.
IL-1ra 또는 이와 기능상 동등한 것의 길항제 작용은 D10 세포들 의존성 IL-1을 사용한 세포에 기초한 IL-1 중화 분석법(실시예 3 참조) 및 기타 표준 IL-1 계열 구성원 중화 분석법에 의해 측정될 수 있다. 어떠한 단백질 제제에 대한 IL-1ra 융합은 분자량(molecular weight)을 증가시키고 체내의 생화학적 수명 증가를 야기시킨다. 면역글로불린 Fc(예를 들면, IgG1 Fc)를 통한 기타 분자들에 대한 IL-1ra 융합은 분자량을 추가로 증가시킬 수 있다. 면역글로불린 Fc의 이합체화기능 때문에 이의 존재는 관심부위에서의 융합된 단백질들의 수치를 두배로 할 수 있다.
TNF
종양괴사인자-알파(TNF 알파) 및 종양괴사인자-베타(TNF 베타)는 수많은 세포 유형에 대한 광범위한 효능의 다양성을 유도하는 기능이 있는 포유류 분비 단백질들이다. 이러한 두 사이토카인의 구조적 및 기능적 특성에서의 커다란 유사성은 "TNF"라는 집합적 호칭을 이끈다.
TNF는 TNF 반응성 세포들의 원형질막 상에 발현된 특이적인 TNF 수용체(TNFR)에 결합함으로써 세포들에 대한 생화학적 영향을 개시한다. TNFR들의 두가지 구별되는 형태가 공지되었다: 약 55킬로달턴(kd)의 분자량을 가지는 타입I TNFR(TNFRI), 및 약 75kd의 분자량을 가지는 타입II TNFR(TNFRII)이다. TNFRI 및 TNFRII 각각은 TNF 알파 및 TNF 베타 양자에 결합한다.
염증성 질병에 있어서의 TNF의 역할은 잘 확립되어있다. 인간 IgG1 Fc 분절(상표명 Enbrel)에 융합된 TNFRII는 류마티스 관절염(rheumatoid arthritis) 및 건선(psoriasis)과 같은 특정 TNF 의존성 장애를 치료하는데 사용되어왔다.
TNF 길항제들이 확인되었다. 용해성 TNFRII 및 TNFRI과 같은 이러한 길항제들은 TNF에 결합하여 TNF가 TNF 수용체에 결합하는 것을 방지한다. 이러한 단백질들은 TNF에 의해 발생하는 생화학적 작용들을 억제하는데 사용될 수 있다. 단백질에 기초한 TNF 중화제들은 IL-1ra 또는 이와 기능상 동등한 것에 융합될 수 있다. IL-1과 같이 TNF는 염증반응의 중요한 조절자이다. 앞서 언급한 TNF 중화제들은 TNF 및 이와 기능적으로 이와 동등한 것을 포함한다. 이들 각각은 하나 이상의 TNF 중화 영역들, TNF를 중화 즉, TNF의 활성을 억제하는 기능이 있는 영역을 포함한다. TNF 중화제 영역은 인간 TNFRII의 세포외 영역, TNFRI의 세포외 영역 또는 항TNF 항체의 다양한 영역들을 포함할 수 있다. 예로는 TNF 수용체 타입II(TNFRII)의 세포외 영역, TNF 결합 단백질 1(rhTBP-1) 또는 TNF 수용체 타입I(TNFRI), 인간화된(humanized) 항TNF 항체(예를 들면, 휴미라(Humira), 애봇(Abbot) 연구소) 및 항TNF 항체 키메라(예를 들면, 존슨&존슨의 레미케이드(Remicade))가 포함된다.
TNF 알파 및 IL-1이 염증성 질병들의 두 주역이므로, TNF 길항제 및 IL-1ra 또는 이와 기능상 동등한 것의 융합 또는 키메라는 TNF 알파 및 IL-1 모두의 통로를 봉쇄하는데 사용될 수 있고, 따라서 급성 또는 만성 염증 관련 질병들을 각개개일 때보다 더 효과적으로 치료하는데 사용될 수 있다. 키메라 단백질의 TNF 중화제 작용은 L979세포(ATTC)와 같은 TNF 의존성 세포들을 이용하여 측정할 수 있다. 더욱 구체적으로는, TNF 의존성 세포들은 유전자 재조합 TNF 알파의 유효복용량에 의해 사멸될 수 있다. 이러한 TNF 의존성 작용은 이러한 TNF 중화제들을 반응에 첨가함으로써 중화될 수 있다. 이러한 TNF 중화제들의 작용은 또한 TNF를 사용하여 체외 결합 분석법에서 측정될 수 있다.
IL-1ra 및 TNF 수용체 타입I(타입II는 아님)의 동시사용이 TNF 알파 및 IL-1 중개성 질병들의 치료에 제안되어왔다. 그러나, 2003년의 이뮤넥스사 및 암젠사에 의해 출판된 242환자들에 대한 24주간의 임상실험결과 엔브렐(Enbrel) 및 키네레트를 비감소된 개별 복용량으로 동시에 사용하는 것은 엔브렐 또는 키네레트 단독처방보다 효능을 증가시키지 않고 높은 감염발생 및 뉴트라페니아(neutrapenia)를 야기시킨다고 결론지어졌다.
IL
-18 및
IL
-4
전술한 IL-1ra 또는 이와 기능상 동등한 것은 또한 기타 항-염증, 항-천식, 또는 항-혈관형성 단백질들에 융합될 수 있다. 예로는: (i)IL-18 결합 단백질(IL-18bp), IL-18 수용체(IL-18R) 세포외영역 및 인간화 항IL-18항체와 같은 IL-18 중화제들; (ii)IL-4 수용체(IL-4R) 세포외영역(상표명 뉴벤스(Nuvance), 이뮤넥스사) 및 인간화 IL-4항체(단백질 디자인 연구소)와 같은 IL-4 중화제들; (iii)Tie2 세포외영역에 가용성인 항-VEGF 항체들 및 안지오포이에틴. 논의한 바와 같이 이러한 단백질들의 C-말단에 IL-1ra를 첨가하면 (1)그들의 분자량이 증가되고; (2)포유류 숙주내에서 생산될때 두개의 당화부위를 더욱 추가하며; (3)주도적 운반으로 그들을 IL-1 수용체가 풍부한 염증 부위로 인도하고; (4)1:1 몰비에서 IL-18, IL-4, VBEGF, 또는 안지오포이에틴 및 IL-1을 동시에 봉쇄한다.
유전자 재조합 IL-18bp는 건선의 징조인 피부염증을 치료하기 위해 임상실험되어왔다(Serono). IL-18bp의 우수한 안전성이 확인되었다. 이것의 C-말단에서의 IL-1ra 융합은 생화학적 수명을 현저히 증가시킨다. IL-1ra 융합을 경유한 염증 부위 지향은 이의 효능을 현저히 증가시킨다. IL-1ra 융합에 의한 IL-18 및 IL-1의 이중중화는 건선과 같은 염증 의존성 질병들의 치료에 시너지효과를 가진다(유도 K 등, 2004). 매우 흥미롭게도, IL-18 및 IL-1은 동일한 IL-1 수용체 계열 및 거의 동일한 시그널 변환 통로를 사용한다. IL-1 및 IL-18의 이중봉쇄는 IL-1 수용체 계열 중개된 전체의 염증 과정을 거의 완벽하게 봉쇄한다. 본 발명의 키메라 단백질에 의한 IL-1 및 IL-18의 이중봉쇄는 가장 효과적인 항 염증성 치료제를 대표한다.
IL-18bp와 기능상 동등한 것도 본 발명의 실시에 이용될 수 있다. IL-18bp 및 이와 기능상 동등한 것은 IL-18bp 중화제 영역, IL-18bp을 중화, 즉 IL-18bp의 활성을 억제하는 기능을 가진 영역을 포함한다. 예를 들면 IL-18bp 중화제 영역은 인간 IL-18 수용체의 세포외영역(미국 특허 6,584,764), IL-18bp, 항IL-18항체, 또는 IL-18 돌연변이 길항제 단백질을 포함할 수 있다.
본 발명의 키메라 단백질의 IL-18 중화작용은 IL-18의존성 KG-1세포들을 이용하여 측정될 수 있다. 예를 들면, 인간 IL-18은 KG-1 세포들로부터 양에 의존적인 방식으로 IFN-g 분비를 유발한다(TNFa의 존재하). 이러한 IL-18 의존성 IFN-g 분비는 유효량의 IL-18 중화제에 의해 억제될 수 있다. 이러한 IL-18 중화제들의 작용은 또한 IL-18/IL-18수용체 결합 분석법에 의해 측정될 수 있다.
용해성 유전자 재조합 IL-4 수용체는 천식의 치료를 위해 임상실험되어왔다. 우수한 안전성이 확인되었다. 그러나, 그 효능은 만족스럽지 못하다. 흥미롭게도, 알레르기항원(allergen)-특이적인 Th2세포 활성 및 기도과민성 반응의 발달에 IL-1이 요구된다는 것이 발표되었다. 또한, 천식과 만성염증 사이의 공존 또는 동시의존성 및 상호작용은 병동에선 매우 일상적이다. IL-1을 봉쇄하는 것은 적어도 동물 모델에 있어서는 천식에 명백한 치료효과를 가진다. 1:1 몰비율의 IL-1ra 가용성 IL-4 수용체 융합에 의한 IL-4 및 IL-1을 동시에 봉쇄하는 것은 심한 천식을 치료하는 효능을 현저히 향상시킨다는 것이 매우 그럴듯하다. IL-1ra의 염증성부위 지향은 염증에 의해 복합된 심한 천식을 치료하는데 있어서 가용성 IL-4 수용체의 치료적 가치를 추가로 상승시킬 수 있다. 또한, IL-1ra 융합은 가용성 IL-4 수용체의 생화학적 수명을 현저히 증가시킬 수 있다.
가용성 IL-4 수용체 또는 이와 기능상 동등한 것은 IL-1ra에 융합될 수 있다. IL-4 수용체 또는 이와 기능상 동등한 것은 IL-4 중화제 영역, IL-4를 중화, 즉 IL-4의 활성을 억제하는 기능을 하는 영역을 포함한다. 예를 들면, IL-4 중화제 영역은 인간 IL-4 수용체의 세포외영역, 항IL-4항체들, 또는 이중변이 I121D/Y124D를 가지는 IL-4 변종 단백질 대항체를 포함할 수 있다(Schnarr 등, 1997). 흥미롭게도, 이러한 IL-4R 서브유닛은 IL-4 및 IL-13수용체의 공유된 공통의 서브유닛의 특성으로 인해 IL-4뿐만 아니라 IL-13에도 결합한다.
본 발명의 키메라 단백질의 IL-4중화제 작용은 IL-4 의존성 TF-1 세포에 기초한 분석법을 통해 측정될 수 있다. 예를 들면, TF-1 세포의 인간 IL-4 의존성 증식은 유효량의 IL-4를 첨가함으로써 억제될 수 있다. IL-4 중화제들의 작용은 또한 IL-4/IL-4 수용체 결합 분석법에 의해 측정될 수 있다.
VEGF
및 안지오포이에틴(
Angiopoietin
)
전술한 접근법은 VEGF 및 안지오포이에틴의 길항제뿐만 아니라 이와 기능상 동등한 것에도 적용될 수 있다. VEGF는 혈관생성에 중요하다. 항-VEGF항체(상표명 Avastin, 진테크사)가 암의 징후를 치료하기 위해 사용되어왔다. 유사하게, IgG1Fc와 융합된 가용성 VEGF 수용체 세포외영역은 혈관생성이 연관된 징후들에 대해 VEGF를 중화하기 위해 사용되어왔다. VEGF와 기능상 동등한 것은 VEGF 중화제영역, VEGF를 중화하는, 즉, VEGF의 활성을 억제하는 기능을 가진 영역을 포함한다. 예를 들면, VEGF 중화제 영역은 인간 VEGF의 세포외영역 및 항VEGF항체의 다양한 영역을 포함할 수 있다.
본 발명의 키메라 단백질의 VEGF 중화 작용은 VEGF 의존성 HUVEC 세포들을 이용하여 측정될 수 있다. 예를 들면, 인간 VEGF는 HUVEC 세포들의 증식을 유발한다. 이러한 HUVEC 세포들의 VEGF 의존성 증식은 유효량의 VEGF 중화제에 의해 억제될 수 있다. VEGF 중화제의 작용은 또한 VEGF/VEGF수용체 결합 분석법을 이용하여 측정될 수 있다.
안지오포이에틴 가용성 수용체 Tie2는 암 또는 혈관생성-연관 류머티스 관절염에 대하여 항-혈관생성 치료제로서 제안되어왔다. 혈관생성 및 염증의 공존 및 동시의존성은 병동에서 오랜동안 연구되어왔다. 가장 일반적인 예는 혈관생성 및 염증이 공존하는 류머티스 관절염이다. 안지오포이에틴 가용성 수용체 Tie2 또는 이와 기능상 동등한 것은 안지오포이에틴을 중화하는, 즉, 안지오포이에틴 1의 활성을 억제할 수 있는 안지오포이에틴 중화제영역을 포함한다. 예를 들면, 안지오포이에틴 중화제영역은 인간 Tie2 및 항Tie2 또는 안지오포이에틴 항테들의 세포외영역을 포함할 수 있다.
본 발명의 키메라 단백질의 Tie-2 중화제 작용은 Tie-2 의존성 HUVEC 세포들에 의해 측정될 수 있다. 예를 들면, 인간 안지오포이에틴 1은 HUVEC 세포들의 세포간 인산화를 유발한다. 이러한 HUVEC 세포들의 Tie-2 의존성 인산화는 유효량의 Tie-2 중화제들에 의해 억제될 수 있다. Tie-2 중화제들의 작용은 또한 Tie-2/안지오포이에틴 2 결합 분석법을 사용함으로써 측정될 수 있다.
IL-1은 중요한 병리학적 혈관생성 자극제로 알려져있다. IL-1ra 및 이와 기능상 동등한 것에 의한 IL-1의 중화는 동물모델 내에서의 혈관생성 및 종양성장을 억제하는데, 이는 염증이 혈관생성을 강화함을 제시하는 것이다. 예를 들면, 유방암 중 가장 공격적인 유형은 염증성 유방암이다. IL-1ra 및 혈관생성제(예를 들면, 항-VEGF항체, 가용성 VEGF 수용체 세포외영역, 또는 가용성 Tie2 세포외영역)의 융합을 이용하는 것은 암 또는 류머티스 관절염이 연관된 징후들을 치료하는데 항-혈관생성제 단독의 경우보다 현저하게 나은 효능을 가진다.
전술한 치료제에 더하여, IL-1ra 또는 이와 기능상 동등한 것에 융합될 수 있는 기타 적절한 단백질 치료제가 아래 나열되었다:
1. E25(olizumab). E25는 알레르기성 천식, 계절성 알레르기성 비염을 치료하는 인간화된 항 IgE 항체(Novartis)이다.
2. H5G1.1. H5G1.1은 건선 및 자가면역질병을 치료하는데 사용될 수 있는 인간화된 항-C5항체(Alexion 제약)이다.
3. TP10. TP10은 급성 호흡곤란증후군의 치료 및 기관 이식을 위한 가용성 보충 수용체 1(sCR1)이다(AVANT 면역치료제).
4. ABX-IL8. ABX-IL8은 건선을 치료하는데 사용될 수 있는 항IL-8 단일클론성 항체(Abgenix)이다.
5. CTLA4Ig. CTL4Ig는 면역억제에 사용될 수 있는 유전재 재조합 가용성 수용체(Bristol-Myers Squibb)이다.
전술한 제제 중 하나와 IL-1ra/기능상 동등한 파트너의 융합에 있어서, 두 융합 파트너들은 각각 상승적인 또는 상호보완적인 작용들을 가진다. IL-1ra는 IL-1 수용체들에 결합하여 융합된 치료제를 IL-1 수용체가 풍부한 염증부위로 인도한다. 이는 또한 IL-1 활성을 중화한다. IL-1ra 및 이러한 단백질 중 어느것과의 융합은 염증, 천식, 및 혈관생성-연관 장애들 또는 내피세포 증식-연관 장애들을 치료하는데 사용될 수 있다.
혈관생성-연관 장애들은 혈관생성을 필요로 하거나 또는 비정상적인 혈관생성을 보이는 어떠한 장애들을 가리킨다. 예로는 암들, 고형종양(solid tumor), 종양전이, 혈관종과 같은 양성종양, 청신경종(acoustic neuroma), 신경섬유종, 트라코마 또는 화농성 육아종, 류머티스 관절염, 건선, 당뇨성 망막병증과 같은 안각성 질병들, 미숙아 망막병증(retinopathy of prematurity), 황반변성(macular degeneration), 각막이식 거부, 신생혈관녹내장(neovascular glaucoma), 수정체후부 섬유증식증(retrolental fibroplasia) 및 피부홍조, 오슬러-웨버 신드롬, 심근성 혈관생성, 플라크 신생혈관증식(plaque neovascularization), 모세혈관확장(telangiectasia), 관절 혈우병(hemophiliac joint), 혈관섬유종 및 육아를 포함하나, 이에 제한되는 것은 아니다. 본 명세서에 기재된 바와 같이, 내피세포 증식-연관장애들은 장폐색, 죽상동맥경화증(atherosclerosis), 피부경화증(scleroderma) 및 비대흉터(hypertrophic scar)를 포함하나, 이에 제한되는 것은 아니다. 명세서 내에 기재된 융합 단백질은 배아이식에 요구되는 신생혈관증식을 방지함으로써 앞서 나열한 질병들을 치료하는데 사용될 수도 있다.
바람직하게는, 본 발명의 융합 단백질은 이합체화 영역을 포함한다. "이합체화 영역"은 두 폴리펩타이드들을 결속시키는 기능을 가진 영역을 가리킨다. 예를 들면, 이합체화 영역은 IgG Fc 분절(예를 들면, 인간 IgG 중사슬 불변영역)을 포함할 수 있다. 이러한 Fc 분절의 예는 SEQ ID No: 2를 포함한다. IgG Fc분절은 사슬간 이황화결합(공유결합)의 형성을 위해 자신의 시스텐인 잔기를 통해 이합체화한다. 때때로 이황화결합을 포함하지 않는 비공유결합 이합체도 발생한다. 이합체된 IgG Fc 분절은, 예를 들면 자신의 N-말단에 두개의 기능성 TNFRII 또는 가용성 IL-4R 또는 IL-18bp 또는 가용성 Tie-2분자들 및 C-말단에 두개의 기능성 IL-1ra 분자들을 제공하는 기능이 있다. 이러한 배열은 TNF 알파 또는 IL-4 또는 IL-18 또는 안지오포이에틴 및 IL-1수용체들을 중화하기 위해 체내 수용체/리간드 결합기회를 증가시킨다.
이황화결합을 통한 공유결합 이합체의 작용은 감소 및 비감소 SDS 페이지 전기영동을 이용하여 측정될 수 있다. 감소조건이 이용될 경우 단백질의 분자량은 반으로 줄여야한다. 비공유성 이합체는 전기영동을 위해 천연의 및 변성된 조건을 이용하여 측정될 수 있다. 이러한 경우, 변성조건이 이용될때는 단백질의 분자량은 반으로 줄여야한다.
본 발명의 폴리펩타이드에 있어서, TNF 중화제영역 또는 IL-4/IL-13 중화제영역 또는 IL-18중화제영역 또는 VEGF 중화제영역 또는 안지오포이에틴 중화제영역, 이합체화 영역, 및 IL-1 수용체 길항제 영역들은 수술적으로 연결될 수 있다. 본 명세서에서, "수술적으로 연결"이란 각 영역의 작용을 방해하지 않는 폴리펩타이드의 구조적인 배치를 가리킨다. 예를 들면, IL-4 중화제영역은 IL-4를 중화하는 기능을 보유한다; 인터류킨-1 수용체 길항제 영역은 IL-1 수용체에 특이적으로 결합하여 세포성 수용체들의 IL-1에 대한 활성을 방지하는 기능을 보유한다; 그리고, 이합체 영역은 본 발명의 두 폴리펩타이드들, 예를 들면, N-말단에 두개의 기능성 IL-4수용체 세포외영역 및 C-말단에 두개의 기능성 IL-1ra 분자들을 결속시키는 기능을 보유한다.
전술한 TNF 중화제들, IL-18 중화제들, IL-4 중화제들, VEGF 중화제들, 또는 안지오포이에틴 중화제들 중 하나의 C-말단에 IL-1ra를 융합시키는 것은 (1)분자량의 증가; (2)포유류 숙주내에서 생산될 때, IL-1ra 분자상에 2개의 당화 부위를 더욱 첨가; (3)중화제를 IL-1 수용체가 풍부한 염증부위로 주도적으로 운반; 및 (4)IL-1 및 TNF, IL-18, IL-4, IL-13, IgE, VEGF, 및 안지오포이에틴을 1:1 몰비율로 동시에 봉쇄한다. 결과적인 이중봉쇄는 염증성 질병들에 더 나은 효능을 가지며, 염증성 질병 과정에 더욱 완벽한 봉쇄를 제공한다. IL-4/IL-13/VEGF/안지오포이에틴 및 IL-1의 동시 이중봉쇄는 염증 및 천식 또는 혈관생성의 공존 및 동시의존성이 질병과정에 중요한 역할을 하는 질병들의 치료에 더 낫고 더욱 완벽한 효능을 가진다.
본 발명의 폴리펩타이드는 합성 또는 유전자 재조합 단백질에 의해 얻어질 수 있다. 유전자 재조합 폴리펩타이드를 제조하기 위해, 이를 암호화하는 핵산이 융합단백질, 예를 들면 글루타티온-S-전이효소(GST), 6x-His 항원결정인자 태그, 또는 M13 유전자 3 단백질을 암호화하는 다른 핵산에 연결될 수 있다. 결과물인 핵산은 적절한 숙주세포들 내에 당 분야에 공지된 방법에 의해 분리될 수 있는 융합 단백질을 발현시킨다. 다양한 숙주-발현 벡터 시스템이 사용될 수 있다. 이들은 유전자 재조합 대식세포 DNA, 플라스미드 DNA, 또는 코스미드 DNA 발현벡터로 변환된 박테리아; 유전자 재조합 효모 발현벡터로 변환된 효모; 및 유전자 재조합 바이러스 또는 플라스미드 발현벡터들로 감염된 인간세포주를 포함하나, 이에 제한되는 것은 아니다. 유전자 재조합 폴리펩타이드들 또는 이의 분절들의 분리 및 정제는 조제용 크로마토그래피(preparative chromatography) 및 단일클론성 또는 다중클론성 항체들을 포함하는 면역학적 분리를 포함하는 종래의 방법으로 수행될 수 있다. 분리된 융합 단백질은 융합파트너를 제거하고 본 발명의 유전자 재조합 폴리펩타이드를 얻기 위해 예를 들면 효소성 분해에 의해 추가적으로 처리될 수 있다.
조성물들 및 치료방법들
유효량의 본 발명의 융합단백질을 필요로하는 대상에게 투여함으로써 과잉면역반응으로 특징지어지는 장애 또는 혈관생성-연관 장애들의 치로법도 본 발명의 범위내에 있다. 치료될 대상은 과도한 또는 원치않는 면역반응에 의해 특징지어지는 질환을 가지고 있거나 또는 얻을 위험이 있는 것으로 인식될 수 있는데, 예를 들면 자가면역 질병, 이식거부, 알레르기성 질병, 또는 면역세포-유도 암으로 고통받는 환자들이다. 본 방법은 단독으로, 또는 기타 약 또는 치료와 연계하여 수행될 수 있다.
"치료"라는 용어는 치유, 완화, 경감, 회복, 예방, 또는 장애, 장애의 증상, 장애의 이차적인 질병단계의 개선, 또는 장애에 앞선 조치의 목적으로 대상에게 화합물을 투여하는 것을 가리킨다. "유효량"은 치료받는 대상에게 의학적으로 바람직한 결과를 일으킬 수 있는 화합물의 양이다. 의학적으로 바람직한 결과는 객관적(즉, 몇몇 실험 또는 지표로써 측정가능) 또는 주관적(즉, 대상이 효과의 징후 또는 느낌을 제공)이다. 치료되는 예시적인 질병들은 급성 및 만성 염증, 당뇨병, 관절염(류머티스 관절염, 소아 류머티스 관절염, 골관절염, 및 건선관절염 포함), 다중 경화증, 뇌척수염, 중증 근육무력증, 계통적 홍반성 루푸스, 자가면역 갑상샘염, 피부염(이토피성 피부염 및 습진 피부염 포함), 건선, 스죄그렌 신드롬, 크론병, 아프타궤양(aphthous ulcer), 홍채염, 결막염, 각막결막염, 타입I 당뇨, 염증성 창자병, 궤양대장염, 천식, 알레르기성 천식, 피부 홍반성 루푸스, 피부경화증, 질염, 직장염, 약물 발진, 나병 역전반응, 나병결절홍반, 자가면역 포도막염, 알레르기성 뇌척수염, 급성 괴사출혈뇌병증, 특발성 양쪽성 점진적 감각신경 청각손실(idiophthic bilateral progressive sensorineural hearing loss), 재생불량 빈혈, 진정적혈구계 빈혈, 특발성 저혈소판증, 다발연골염, 베게너 육아종, 만성 활성 간염, 스티븐스-존슨 신드롬, 특발성 스프루(sprue), 편평태선(lichen planus), 그레이브병, 사르코이드증, 원발쓸개간경화증(primary biliary cirrhosis), 후방궤양(uveitis posterior), 간질성 폐섬유증, 이식대숙주병, 골수이식과 같은 이식의 경우(동종 또는 이종 조직을 이용한 이식 포함), 간 이식, 또는 어떤 기관 또는 조직의 이식, 아토피성 알레르기와 같은 알레르기들, AIDS, 백혈병 또는 림프종과 같은 T세포 신생물종양(neoplasm), 급성 간염, 혈관생성 관련 질병들(류머티스 관절염 및 암과 같은), 및 심장혈관질병을 포함한다.
치료될 대상은 전술한 하나 이상의 질환의 치료가 필요한 것으로 인식될 수 있다. 이러한 치료를 필요로 하는 대상을 분간하는 것은 대상, 또는 건강보호 전문가의 판단으로, 및 객관적(즉, 실험 또는 진단법에 의해 측정가능) 또는 주관적(즉, 의견)일 수 있다.
한 체내접근법에서, 치료용 조성물(예를 들면, 본 발명의 융합 단백질을 포함한 조성물)이 대상에게 투여된다. 일반적으로는, 단백질이 약학적으로 수용가능한 담체(예를 들면 생리 식염수)에 부유화되어 경구투여 또는 정맥주사, 또는 피하, 근육간, 경막내, 복막내, 직장내, 질내, 비강내, 장내, 기관내 또는 폐내주사 또는 이식에 의해 투여된다.
요구되는 복용량은 투여경로의 선택; 조성물의 특성; 대상의 질병의 특성; 대상의 체격, 체중, 표면적, 연령 및 성별; 기타 투여되는 약물; 및 담당의사의 판단에 의존한다. 적절한 복용량은 0.01-100.0mg/kg이다. 요구되는 복용량의 다양성은 활용되는 조성물의 다양성 및 다양한 투여경로의 상이한 효과의 관점에서 예상된다. 예를 들면, 경구투여는 정맥주사보다 많은 양의 복용이 예상된다. 이러한 복용치의 다양성은 업계에서 잘 이해되는 대로 최적화를 위한 표준 실험 순서를 이용하여 조절될 수 있다. 적절한 수송 운반체(예를 들면, 미세입자들 또는 이식가능 장치)내로의 캡슐화는 운반의 효율을 증가시킬 수 있는데, 구체적으로는 입을 통한 운반이다.
약학적으로 수용가능한 담체 및 본 발명의 단백질의 유효량을 포함하는 약학적 조성물도 본 발명의 범위 내에 있다. 약학적 조성물은 전술한 질병들을 치료하는데 사용될 수 있다. 약학적으로 수용가능한 담체는 용매, 분산매체, 코팅, 항박테리아 및 항균제, 및 등장(等張)제 및 흡수지연제를 포함한다.
본 발명의 약학적 조성물은 종래의 방법을 활용할 수 있는 상이한 투여경로를 위한 복용형태로 조성될 수 있다. 예를 들면, 캡슐, 겔 밀봉재, 또는 경구투여를 위한 정으로 조성될 수 있다. 캡슐들은 젤라틴 또는 셀룰로오스와 같은 어떠한 약학적으로 수용가능한 표준적 물질들을 포함할 수 있다 정은 조성물과 고형담체 및 윤활제의 혼합물을 압축함으로써 종래의 방법들에 따라 조성될 수 있다. 고형담체의 예로는 전분 또는 당 벤토나이트가 포함된다. 조성물은 결합제, 예를 들면 락토오스 또는 만니톨, 종래의 충진재, 및 정제(tableting agent)를포함하는 단단한 껍질의 정 또는 캡슐의 형태로 투여될 수 있다. 약학적 조성물은 비경구적 경로를 통해 투여될 수 있다. 비경구적 복용형태의 예로는 수성용액, 등장(等張)성 식염수 또는 활성화제의 5% 글루코오스, 또는 기타 잘 알려진 약학적으로 수용가능한 부형제가 포함된다. 사이클로덱스트린 또는 당 분야에 익숙한 사람들에게 잘 알려진 기타 용해제가 치료제의 운반을 위해 약학적 부형제로서 활용될 수 있다.
본 발명의 조성물의 효능은 체내 및 체외 양쪽으로 평가될 수 있다. 예를 들면, 다음을 참조할 수 있다. 간략히, 조성물은 체외의 면역반응을 억제하는 능력이 실험될 수 있다. 체내 실험을 위해서는, 조성물은 동물(예를 들면, 생쥐모델)에 주사될 수 있고, 그 치료효과가 평가된다. 결과에 근거하여, 적절한 복용범위 및 투여경로가 결정될 수 있다.
다음의 예들은 단순히 묘사하기 위해 고려된 것이고, 어떠한 방식으로든 설명의 남은부분을 제한하는 것은 아니다. 더이상의 설명 없이도 당 업계의 기술자는 본 명세서의 상세한 설명에 기초하여 본 발명의 모든 내용을 활용할 수 있을 것으로 믿어진다. 본 명세서 내에 인용된 모든 출판물들은 전체내용이 참증으로서 통합되었다.
실험결과는 포유류 숙주들 내에서 만들어진 IL-1ra가 융합된 분자들은 당화된 IL-1ra를 포함하고, IL-1ra가 융합되지 않은 분자보다 큰 분자량을 가진다는 것을 가르쳐준다. 이들은 더 긴 생화학적 수명 및 덜 빈번한 효과적인 주사복용을 가진다. 이의 염증부위-지향특성 및 적은 효과적 복용량 및 낮은 복용빈도 덕분에 IL-1ra가 융합된 분자는 IL-1ra가 융합되지 않은 분자들 또는 IL-1ra가 융합되지 않은 분자와 IL-1ra를 함께 사용하는 것보다 적은 부작용을 가질 수 있다.
도 1: 혈청배제 배지 내의 24구멍판(well plate); 직접적인 쿠마시(Coomasie) 블루 단백질 염색법; 모든 유전자 재조합 단백질들은 0.5-1.0㎍ 범위의 가시성; 1줄당 10-15㎕ 분배;인 TNFRII-Fc 및 TNFRII-Fc-IL-1ra 키메라의 CHO 세포 클론의 제1세대 생산.
도 2: 쿠마시 블루 염색법; 감소 및 비감소 조건의 SDS 페이지;인 TNFRII-Fc-IL-1ra 키메라의 친화정제법(affinity purification).
도 3: 제1 정제단계-완전한 또는 TNFRII-Fc 조절에 의해 부분적으로 감쇠된 TNFRII-Fc-IL-1ra 키메라의 HPLC 분석의 변화에 의한 TNFRII-Fc-IL-1ra 키메라의 감쇠 문제를 감소시키는 문제해결(trouble shooting)의 예.
도 4: IL-4R-Fc, IL-4R-Fc-IL-1ra 및 IL-18bp-Fc-IL-1ra의 친화정제법.
도 5: 세포에 기초한 TNF 알파 중화 테스트가 표지된 TNFRII-Fc(엔브렐(Enbrel))와 유사하게 TNFRII-Fc-IL-1ra 키메라가 TNF 알파의 L979 세포들에 대한 사멸작용을 중화한다는 것을 나타낸다.
도 6: 세포에 기초한 IL-1 중화 테스트가 표지된 IL-1ra(Kineret) 및 TNFRII-Fc-IL-1ra 키메라 모두가 D10 세포 증식에 대한 IL-1의 생화학적 작용을 중화한다는 것을 가리킨다.
도 7: IL-4R-Fc-IL-1ra 및 대조군 IL-4R-Fc의 인간 IL-4 중화 분석.
도 8: IL-4R-Fc-IL-1ra의 인간 IL-1 중화 분석.
도 9: IL-18bp-Fc-IL-1ra의 IL-18 중화작용.
도 10: IL-18bp-Fc-IL-1ra의 IL-1 중화작용.
도 11: D10 세포들 내에서의 VEGFR1-Fc-IL-1ra의 IL-1 중화작용.
도 12: HUVE 세포들 내에서의 VEGFR1-Fc-IL-1ra의 VEGF 중화작용.
도 13: IL-1 수용체 결합 분석.
실시예
1
다양한 발현 벡터들이 생성되었다. 이 벡터들 각각은 다음 단백질을 암호화 한다:
A) TNFRII-Fc-IL-1ra(SEQ ID NO:5), TNFRI-Fc-IL-1ra(SEQ ID NO:8) 및 대조군 TNFRII-Fc(SEQ ID NO:4) 또는 TNFRI-Fc(SEQ ID NO:7);
B) 휴미라(D2E7)-IL-1ra(SEQ ID NO:10 및 11), 레미케이드(cA2)-IL-1ra(SEQ ID NO:13 및 14), 및 레미케이드(cA2)(SEQ ID NO:12 및 14);
C) IL-18bp(SEQ ID NO:15), 이합체화된 IL-18bp-Fc(SEQ ID NO:16), 및 이합체화된 IL-18bp-Fc-IL-1ra(SEQ ID NO:17);
D) 가용성 IL-4R 세포외영역(SEQ ID NO:19), IL-4R-Fc(SEQ ID NO:19), 및 IL-4R-Fc-IL-1ra(SEQ ID NO:21);
E) VEGFR1-Fc-IL-1ra 및 경사슬(SEQ ID NO:24 및 23) 및 VEGFR중사슬-IL-1ra 및 경사슬(SEQ ID NO:25 및 23).
단백질을 암호화하는 대부분의 구성(SEQ ID NO: 4-25)이 서열화되었고 포유류 세포주 내에서 발현되었다. SEQ ID NO: 4-25는 천연 또는 최적화된 코돈 및 인공 또는 천연의 분비 시그널 시퀀스 중 하나를 이용해 포유류 숙주에 적용된 서스펜션 내에서 발현되었다. 이합체화된 항체 생성물들은 비가열된 SDS 페이지 겔 및 웨스턴 블럿에 의해 검출되었다.
24구멍판(well plate) 내의 혈청배제배지 내의 TNFRII-Fc(SEQ ID NO:4) 및 TNFRII-Fc-IL-1ra(SEQ ID NO:5)의 발현 규정농도는 각각 50mg-100mg/L(도 1)에서 발견되었다. CHOK1 세포들(조건부 배지의 직접 쿠마시 블루 단백질 염색법에 의해 측정됨)에 적용된 서스펜션 내에서 TNFRII-Fc 보다 TNFRII-Fc-IL-1ra의 많은 발현 이 발견되었다. 이러한 결과는 IL-1ra가 융합된 키메라 단백질이 포유류 숙주 내에서 상업적으로 충분한 높은 레벨로 생산될 두 있음을 가리킨다.
실시예
2
TNFRII-Fc-IL-1ra, IL-4R-ECD-Fc-IL-1ra 및 IL-18bp-Fc-IL-1ra의 정률증가 및 정제가 행해졌다. 세포주는 CHO-CD4 배지(어빈 사이언티픽) 및 사내 공급 배지 내의 혈청배제 서스펜션 내에서 배양되었고 3리터의 생물반응기(bioreactor)(에플리콘) 내에서 정률증가되었다. TNFRII-Fc-IL-1ra(SEQ ID NO:5), IL-4R-ECD-Fc-IL-1ra(SEQ ID NO:20), 및 IL-18bp-Fc-IL-1ra(SEQ ID NO:17)이 상업적 수준으로 생산되었다. 이러한 단백질들은 단백질-A 직접 포획, 이후의 이온교환 및 소수성 크로마토그래피(도 2, 3 및 4)에 의해 정제되었다. 거대 정제 단백질들이 조성, 동결건조 되고 SEC-HPLC분석되었다.
실시예
3
TNFRII-Fc-IL-1ra, IL-4R-Fc-IL-1ra, IL-18bp-Fc-IL-1ra, 및 VEGFR1-Fc-IL-1ra들이 생물분석법으로 실험되었다.
세포에 기초한 IL-1 중화 분석을 위해, IL-1 의존성 D10 세포들(ATCC)이 D10 세포들의 재조합 인간 IL-1의존성 증식에 대한 IL-1ra(키네레트), TNFRII-Fc-IL-1ra, IL-4R-Fc-IL-1ra, 및 IL-18bp-Fc-IL-1ra의 봉쇄작용을 실험하는데 사용되었다.
간략히, 인간 IL-1 알파는 양에 의존적인 방식으로 D10 세포들을 유발하였다. IL-1a가총 세포 성장의 50%를 유발했을때의 농도, 즉 EC50이 측정되었다. D10 세포들에 대한 hIL-1a의 정상적인 EC50범위는 1-5pg/ml였다. 세포들이 유효량의 IL-1 수용체 길항제와 사전 배양되었을 때, IL-1ra는 세포표면 IL-1 수용체들의 봉쇄를 통해 세포증식을 억제하였다. 이러한 봉쇄효과도 역시 양에 의존적이다. 수용체 길항제의 농도가 낮을 때, 이는 세포표면 수용체들을 봉쇄하지 않는다. 그리고는, IL-1은 회복된 세포 증식을 유발한다. 50%의 IL-1 활성이 봉쇄되었을 때의 수용체 길항제 농도가 길항제의 EC50이었다.
유전자 재조합 단백질(TNFRII-Fc-IL-1ra, IL-4R-Fc-IL-1ra, IL-18bp-Fc-IL-1ra, 및 VEGFR1-Fc-IL-1ra)은 가용성 TNFRII, IL-18, IL-4, 또는 VEGF 중화제뿐만 아니라 IL-1 수용체 길항제와 같이 행동하였다. 이러한 세포 기초적인 생물분석법은 이러한 키메라 분자들의 생화학적 작용을 확인시켜주었다(도 6, 8, 10 및 11).
세포 기초 TNF 중화 분석법을 위해, L929 세포들(생쥐 결합세포주, ATCC)이 TNF 알파에 대한 TNFRII의 봉쇄작용을 실험하기 위해 사용되었다. 간략히, TNF 알파(TNF-a)는 신속한 세포 사멸을 양에 의존적인 방식으로 유발하였다. TNF-a의 EC50(TNF-a가 총 세포 사멸의 50%를 유발했을 때의 농도)은 50pg/ml 미만에서 찾아졌다. TNF-a 분자들이 고농도의 가용성 TNF 수용체(sTNFR)와 사전 배양된 경우, 가용성 수용체는 TNF-a에 결합하여 세포표면 수용체들에 대한 이것의 결합을 억제하였다. 이것은 세포 사멸을 유발하는 TNF-a의 작용을 봉쇄하였다. 이러한 봉쇄효과도 양에 의존적이었다. sTNFR의 농도가 특정지점까지 희석되었을 경우 TNF-a의 봉쇄작용이 발견되지 않았고, 세포사멸이 회복되었다. 이에 따라, sTNFR의 EC50(즉, TNF-a 작용의 50%를 봉쇄했을 때의 농도)이 결정되었다.
복제물 내의 인간 TNF-알파(바이오소스)의 연속적 희석물이 10%의 말 혈청 내의 일정수의 L929세포들, L-글루타민 및 1㎍/ml의 악티노마이신 D가 제공된 DMDM배지와 함께 사전에 파종한 96-구멍분석판 내로 총부피 150㎕/구멍으로 가해졌다. 대조군 구멍들(오직 배지 내의 세포들 함유)도 포함되었다. 분석판은 가습된 챔버 내의 37℃ 5% CO2 배양기에서 1일간 배양되었다. 각 구멍의 세포들은 이후 10%의 파라포름알데히드에 고정되었고, 1% 크리스탈 바이올렛 용액으로 염색되었다. 염색시약은 30%의 아세트산에 용해되었다. 세포들의 총 수에 정비례하는 분석판의 각 구멍의 광학밀도(O.D)가 540nm의 파장에서 판 판독기 내에서 읽혀졌다. 세포독성 곡선이 O.D. vs TNF-알파 농도의 관계로 작성되었다. 복제물 내의 TNFRII-Fc(엔브렐) 및 TNFRII-Fc-IL-1ra의 연속적 희석물이 고정된 농도의 10% 말 혈청 내의 인간 TNF-알파, L-글루타민 및 1㎍/ml의 악티노마이신 D가 제공된 DMEM 배지와 96-분석판 내에서 혼합되었다. 분석판은 37℃에서 1시간 동안 사전 배양되었다. 분석판의 각 구멍 내의 혼합물은 일정수의 L020세포들이 사전파종된 다른 96구멍판 내로 이동되었다. 각 구멍 내의 TNF-알파의 최종 농도는 총 부피 150㎕/구멍일 때 500pg/ml였다. 분석판은 가습된 챔버 내의 37℃ 5% CO2 배양기에서 1일간 배양되었다. 각 구멍의 세포들은 이후 10%의 파라포름알데히드에 고정되었고, 1% 크리스탈 바이올렛 용액으로 염색되었다. 염색시약은 30%의 아세트산에 용해되었다. 세포들의 총 수에 정비례하는 분석판의 각 구멍의 광학밀도(O.D.)가 540nm의 파장에서 판 판독기 내에서 읽혀졌다. 중화 곡선이 O.D. vs TNFRII-Fc 및 TNFRII-Fc-IL-1ra의 농도의 관계로 작성되었다.
실험결과는 인간 TNF 알파가 L929세포 사멸을 양에 의존적인 방식으로 유발한다는 것을 보여주었다. 악티노마이신 D만이 함께 있는 세포들을 포함하는 바탕 O.D.는 0.5였다. 인간 TNF-알파 복용량 곡선은 0.5의 기본 수치로부터 0.1의 가장 낮은 수치로 감소되었다. O.D.는 100pg/ml 이상의 인간 TNF-알파 농도로부터 추가로 감소하지 않았는데, 이는 인간 TNF-알파의 포화상태를 가리킨다. 모든 실험들은 복제물 내에서 수행되었고, 각 지점에서의 CV%는 9% 미만이었다. 이러한 조건 하의 인간 TNF-알파의 EC50은 8pg/ml로 결정되었다.
TNFRII-Fc(엔브렐) 및 TNFRII-Fc-IL-1ra는 L929 세포들에 대한 인간 TNF-알파의 작용을 양에 의존적으로 억제하였다. 기본 수치(인간 TNF-알파(500pg/ml) 및 악티노마이신 D의 존재하의 세포들에 대한)의 O.D.는 0.1이었다. 다른 농도의 TNFRII-Fc-IL-1ra 존재하에서 O.D.는 0.1에서 기본수치인 0.5로 상승하였는데, 이는 전체 중화를 가리킨다. TNFRII-Fc 및 TNFRII-Fc-IL-1ra 양자는 50ng/ml의 농도에서 인간 TNF-알파의 작용을 전부 중화하였다. 모든 희석물들이 복제물 내에서 실험되었고, 각 지점에서의 CV%는 10% 미만이었다. 이러한 조건 하의 TNFRII-Fc(엔브렐) 및 TNFRII-Fc-IL-1ra의 EC50은 3-4ng/ml 및 10ng/ml이었다.
세포에 기초한 IL-4 중화제 분석을 위해, 인간 IL-4 유발 TF-1 세포 증식이 이용되었다. TF-1 세포들은 상이한 농도들의 인간 IL-4를 포함하는 배지와 함께 배양되었고, 이후 37℃ 5% CO2 배양기 내의 96-구멍판에서 3일간 배양되었다. MTS가 배양에 추가되고, 5시간 배양되었다. 판의 광학밀도(OD)가 490nm에서 판 판독기 내에서 읽혀졌다. 세포증식 곡선이 작성되었다(OD vs. 인간 IL-4의 농도). 중화를 위해, IL-4R-Fc 및 IL-4R-Fc-IL-1ra의 연속적 희석물이 일정농도의 인간 IL-4(2ng/ml)와 함께 37℃에서 96구멍판 내의 배양배지에서 1시간 동안 사전 배양되었다. 배양이 끝난 후, 동일한 숫자의 TF-1 세포들이 96구멍판의 각 구멍에 가해졌다. 판은 37℃ 5% CO2 배양기 내에서 3일간 배양되었다. MTS가 가해지고 5시간 동안 배양되었다. 판의 OD가 490nm에서 판 판독기 내에서 읽혀졌다. 세포 성장 억제 곡선이 OD vs. IL-4R-Fc 및 IL-4R-Fc-IL-1ra의 농도의 관계로 작성되었다.
IL-1 중화 분석의 결과(도 8)와 함께 취해진 실험결과(도 7)는 IL-4R-Fc-IL-1ra이 기능적이고 IL-4R 및 IL-1 모두의 중화 작용을 가진다는 것을 보여준다.
세포에 기초한 IL-18 중화 분석법을 위해, KG-1세포들로부터 인간 IL-18 유도 IFN-g 분비(TNFa 존재하)가 양에 의존적인 방식으로 사용되었다. 인간 IL-18의 EC50(KG-1세포들의 최대 IFNg 분비의 50%를 유도했을 때의 농도)는 보통 20-40ng/ml이다. 인간 Il-18 결합 단백질(IL18bp)은 세포배양에 적용되기 전에 인간 IL-18과 사전 배양되었고, IL-18bp는 IL-18에 결합하여 그 활성을 봉쇄하였다. 이러한 봉쇄효과는 양에 의존적이었다. 최대 IFNg 분비의 50%가 봉쇄되었을 때의 결합 단백질의 농도는 EC50이다.
복제물 내의 IL-18bp-Fc-IL-1ra 및 대조군 IL-18bp-Fc의 연속적인 희석물이 37℃의 96구멍 배양판 내의 배양배지에서 1시간 동안 일정농도의 인간 IL-18(R&D 시스템)과 사전 배양되었다. 인간 IL-18의 연속적 희석물의 복제물 자체도 양성 대조군으로서 판에 포함되었다. 배양이 끝난 후 동일한 수의 KG-1 세포들(ATCC, CCL246)이 일정량의 인간 TNFa(바이오소스사)와 함께 각 96구멍 분석판에 가해졌다. 분석판은 37℃ 5% CO2 배양기 내에서 24시간 동안 추가로 배양되었다. 배양배지의 50㎕/구멍이 각 분석판의 구멍으로부터 엘리사 판(ELISA plate)으로 이동되었다. 인간 IFNg ELISA(바이오소스사)는 키트의 지시에 따라 실험되었다. 판의 광학밀도(OD)가 450nm에서 판 판독기 내에서 읽혀졌다. 인간 IL-18에 의해 유발된 IFNg 분비 곡선이 OD vs. IL-18bp-Fc-IL-1ra 및 대조군 IL-18bp-Fc의 농도의 관계로 작성되었다.
세포에 기초한 분석결과는 도 9에 나타내었다. IL-1 중화분석의 결과(도 10)와 함께 취하여 기능성 IL-18bp-Fc-IL-1ra 키메라가 성공적으로 제조되었다. 이는 IL-18 및 IL-1 중화작용을 유지하였다.
인간 VEGF(혈관 내피세포 성장인자: vascular endothelial cell growth factor)는 HUVE(인간 배꼽정맥 내피: human umbilical vein endothelial) 세포 증식을 양에 의존적인 방식으로 유발한다. HUVE 세포들의 최대 증식의 50%를 유발했을 때의 인간 VEGF의 농도인 EC50은 보통 2-6bg/ml 사이이다. 가용성 인간 VEGF 수용체-1이 세포배양에 적용되기 전에 인간 VEGF와 함께 사전배양되었을 때, 이 가용성 인간 VEGF 수용체-1은 인간 VEGF에 결합하여 세포들에 대한 그것의 작용을 봉쇄한다. 이러한 가용성 수용체의 봉쇄효과도 양에 의존적이다. 최대 세포증식의 50% 가 봉쇄되었을 때의 가용성 수용체의 농도가 이것의 EC50이다. 유전자 재조합 단백질 VEGFR1-Fc-IL-1ra는 동일분자 상에 가용성 VEGF 수용체 및 IL-1 수용체 모두와 함께 구성되었다. 따라서, 이것은 가용성 VEGFR1뿐만 아니라 IL-1 수용체의 길항제로서 작용할 수 있다.
복제물 내의 VEGFR1-Fc-IL-1ra의 연속적인 희석물이 37℃의 96구멍 배양판 내의 배양배지에서 1시간 동안 일정농도의 VEGF(바이오소스, 10㎕/ml)와 사전 배양되었다. 인간 VEGF의 연속적 희석물의 복제물 자체도 양성 대조군으로서 판에 포함되었다. 배양이 끝난 후 동일한 수의 HUVE 세포들(Cambrex, CC-2517)이 각 96구멍 분석판에 가해졌다. 분석판은 37℃, 5% CO2 배양기 내에서 96시간 동안 추가로 배양되었다. 배양의 마지막 4시간 전에 분석판의 각 구멍에 MTS(프로메가)가 가해졌다. 판의 광학밀도(OD)가 490nm에서 판 판독기 내에서 읽혀졌다. VEGF에 의한 세포증식 곡선이 OD vs. VEGF의 농도의 관계로 작성되었다. VEGF-R 중화곡선이 OD vs. VEGFR1-Fc-IL-1ra의 농도의 관계로 작성되었다.
인간 VEGF는 HUVE 세포들이 증식하도록 양에 의존적으로 자극한다. ED50은 3ng/ml였다. 10ng/ml에서 VEGF가 세포들에 적용되기 전에 VEGFR1-Fc-IL-1ra와 사전배양되었을 때, VEGF 의존성 세포 증식은 양에 의존적인 방식으로 억제되었다. VEGFR1-Fc-IL-1ra의 ED50은 15n/ml였다(도 12). IL-1 중화분석의 결과(도 11)와 함께 취하여, 기능성 VEGFR1-Fc-IL-1ra 키메라가 성공적으로 제조되었다. 이것은 VEGF 및 IL-1 중화작용을 유지하였다.
실시예
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천식 생쥐모델 내에서의 IL-4R-Fc-IL-1ra의 동물실험이 수행되었다. 암컷 BALB/c 생쥐(생후 6-8주)가 사용되었다. 간략히, 이 생쥐들은 2.25mg의 알루미늄 산화물(피어스, 락포드, IL) 내에서 총부피 100㎕로 에멀젼화된 40㎍의 OVA(시그마)로 0일 및 14일에 복막내 주사(ip injection)되었다.
생쥐들은 8시간 군(群)들 및 48시간 군들로 나뉘어졌다. 8시간 군들은 대조 식염수-8hr, OVA-8hr, IL-4R-Fc/OVA-8hr 및 IL-4R-Fc-IL-1ra/OVA-8hr 그룹을 포함하는 반면, 48시간 군들은 대조 식염수-48hr, OVA-48hr, IL-4R-Fc/OVA-48hr 및 IL-4R-Fc-IL-1ra/OVA-48hr 그룹을 포함한다.
28일째, 식염수 대조군 그룹을 제외한 모든 군은 0.05ml의 보통 식염수 내의 OVA 100㎍을 비강내 경로를 통해 주입받았다. 식염수 대조군은 0 및 14일에 보통 식염수를 알루미늄과 함께 복막내 경로로 주입받았고, 28일에 0.05ml의 보통 식염수를 비강내 경로로 주입받았다.
29일째, 식염수 대조군을 제외한 48시간 군들은 0.05ml의 보통 식염수 내의 OVA 100㎍을 비강내 경로를 통해 추가로 주입받았다. 식염수 대조군은 29일에 0.05ml의 보통 식염수를 비강내 경로로 주입받았다.
IL-4R-Fc 및 IL-4R-Fc-IL-1ra의 투여
IL-4R-Fc/OVA-8hr, IL-4R-Fc-IL-1ra/OVA-8hr, IL-4R-Fc/OVA-48hr 및 4R-Fc-IL-1ra/OVA-48hr 그룹들은 28일에 200㎍/생쥐/일을 주입받았다. 이들은 28일에 OVA와의 시도 60분 전에 복막내 주사를 통해 투여되었다. IL-4R-Fc/OVA-48hr 및 4R- Fc-IL-1ra/OVA-48hr 그룹들은 29일에 200㎍/생쥐/일을 추가로 주입받았다.
기관지 폐포 세척(bronchoalveoar lavage: BLA)에서의 세포수의 측정
8시간 군들에 대하여, 28일의 단일 비강내 OVA 시도 8시간 후에 생쥐들은 BAL 유체 및 조직학 연구를 위해 희생되었다. 48시간 군들에 대하여, 28일 및 29일의 2회의 비강내 OVA 시도 48시간 후에 생쥐들이 희생되었다. 왼쪽 폐를 주기관( mainstem bronchus)에서 묶은 후, 오른쪽 폐를 1.0ml의 보통 식염수로 기관 캐뉼라(tracheal cannula)를 통해 세척하였다. 총 수(백혈구)가 혈구계를 이용해 측정되었다. 류코스텟(leukostat: 피셔 Diagnostics, 피츠버그, PA)으로 염색된 세포원심된 조직표본으로부터 상이한 세포수가 계측되었다. 세포들은 표준 혈액 절차에 의해 대식세포, 호산구, 호중구, 및 림프구로 분별되었고, x400 확대하에 적어도 200개의 세포들이 계수되었다.
폐 조직학
기관 및 왼쪽 폐(상엽 및 하엽)가 채취되어 20℃의 카르노이(Carnoy) 용액에서 15시간 동안 고정되었다. 파라핀에 담근 후, 조직들은 5㎛ 분절으로 절단되었다. 각 생쥐들에서, 왼쪽 폐에 걸쳐 임의로 분배된 10개의 기도 조각들이 세포 염증반응의 중증도 및 점액 폐색을 위해 분석되었다. 폐 혈관 및 기도 주위의 세포침윤의 강도가 0-4+ 범위의 반정량저울 상에서 분석되었다.
결과
1. IL-4R-Fc-IL-1ra 처리가 초기의 폐 염증을 차단하였음.
표 1. 단일 비강내 OVA 시도 8시간 후 BAL 유체 내의 상이한 세포수. 대조 식염수-8hr, OVA-8hr, IL-4R-Fc/OVA-8hr 및 IL-4R-Fc-IL-1ra/OVA-8hr 그룹들에서 상이한 세포수가 측정되었다(각 그룹에서 n=5; 평균±표준오차로 주어짐).
| 총 세포수x10-3 | 호중구x10-3 | |
| 식염수 대조군 8hr | 51±8 | 30±5 |
| OVA-8hr | 220±16 | 172±17 |
| IL-4R-Fc/OVA-8hr | 200±11 | 165±10 |
| IL-4R-Fc-IL-1ra/OVA-8hr | 86±7 | 60±8 |
2. IL-4R-Fc-IL-1ra 처리는 또한 말기의 폐 염증도 차단하였음.
표 2. 2회의 비강내 OVA 시도 48시간 후 BAL 유체 내의 상이한 세포수. 대조 식염수-48hr, OVA-48hr, IL-4R-Fc/OVA-48hr 및 IL-4R-Fc-IL-1ra/OVA-48hr 그룹들에서 상이한 세포수가 측정되었다(각 그룹에서 n=5). 평균±표준오차로 주어짐. P<0.01
| 총 세포수x10-3 | 호산구x10-3 | |
| 식염수 대조군 48hr | 44±8 | 3±2 |
| OVA-48hr | 180±12 | 52±7 |
| IL-4R-Fc/OVA-48hr | 102±10 | 20±5 |
| IL-4R-Fc-IL-1ra/OVA-48hr | 68±7 | 10±5 |
폐 조직학 실험
OVA-8hr 및 OVA-48hr 그룹들 모두에서의 폐 혈관 및 기도 주위의 세포 침윤의 강도가 관찰되었다. IL-4R-Fc/OVA-8hr 및 IL-4R-Fc/OVA-48hr와 비교할 때, IL-4R-Fc-IL-1ra-8hr 및 IL-4R-Fc-IL-1ra-48hr 그룹들에서 현저하게 감소된 폐 혈관 및 기도 주위의 세포 침윤이 관찰되었다. 실험결과는 IL-4R-Fc-IL-1r이 동물 모델 내에서의 천식 치료에 최고였다는 것을 제시한다.
실시예
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생쥐 CIA 모델 내에서의 IL-18bp-IgG1Fc-IL-1ra 동물실험이 수행되었다. 생후 8 내지 10주된 DBA/1J 생쥐들에서 소의 콜라겐 타입II(CII)가 최근 설명된 표준 연구계획(바나다 등, 2002)에 따라 진피내 주사됨으로써 CIA가 유도되었다. 각 생쥐는 0 및 21일에 IFA 내의 200㎍의 CII 및 200㎍의 비활성화된 결핵균(Mycobacterium tuberculosis)(Difco, 디트로이트, MI)을 포함하는 100㎕의 주사액을 주입받았다. 21일 및 36일 사이에 생쥐들(n=5)은 3일마다 복막내 주사로서 두가지 중간치료 중 하나를 받았다: PBS 대조, 3mg/kg IL-18bp-Fc, 및 3mg/kg IL-18bp-Fc-IL-1ra. 생쥐들은 36일에 경추골절에 의해 희생되었다. 3마리의 보통 DBA/1J 생쥐(대조군)가 동일 시간에 희생되었다.
21일 및 36일 사이에 각 발에 대하여 CIA의 임상질병활성도가 두명의 실험조건을 모르는 실험자에 의해 3점 등급을 이용하여 격일로 평가되었다: 0=정상 관절; 1=경미한 염증 및 홍조; 2=발 전체에 영향을 미치며 사용을 억제시키는 심각한 홍조 및 부기; 및 3=관절굳음증, 관절경직, 및 기능 상실과 함께 변형된 앞발 또는 관절. 임상질병활성도의 총 점수는 4발 모두에 기초하여 각 동물의 최고점수는 12점이었다(만다 등, 2002).
36일째에 모든 생쥐들로부터 양 앞발 및 우측 뒷다리가 외과적으로 절단되어 조직 샘플의 제조 및 전술한 조직학적 분석과 함께 10% 완충된 포르말린에 고정되었다(벤델 등, 2000). 실험조건을 모르는 숙련된 실험자들에 의해 발, 발목, 및 무릎들에서 발견된 조직학적 관찰점들이 채점되었다. 데이터들은 염증, 판누스(pannus), 연골손상, 및 골 손상에 대한 평균점수뿐만 아니라 총점이 동물당 다섯개의 관절세트 및 0-5등급에 기초하여 전술한 대로 표현되었다(벤델 등, 2000).
결과
임상질병활성도 및 관절 조직학에 대한 IL-18bp-Fc-IL-1ra의 효과
관절염의 발전은 모든 그룹들에서 100% 발생되었다. PBS 대조군과 단독으로 비교할때, 21 및 36일 사이에 3mg/kg IL-18bp-Fc, 및 3mg/kg IL-18bp-Fc-IL-1ra 중 하나로 처리된 쥐들은 임상질병활성도점수의 감소를 보였다(표 1). 관절에 대한 조직학적 분석은 또한 3mg/kg IL-18bp-Fc, 및 3mg/kg IL-18bp-Fc-IL-1ra 중 하나로 처리하는 것은 PBS 그룹에 비해 관절 손상을 예방한다는 것을 나타내었다. 3mg/kg IL-18bp-Fc, 및 3mg/kg IL-18bp-Fc-IL-1ra 사이에서는 임상질병활성도 점수 또는 조직학적 점수 중 하나에서 현저한 상이점이 관찰되었다. IL-18bp-Fc-IL-1ra가 IL-18bp-Fc보다 현저하게 우수하였다(표 1).
표 3: IL-18bp-Fc-IL-1ra로 처리된 CIA 생쥐들의 임상질병활성도.
DBA/1J 생쥐들은 0 및 21일에 IFA 내의 CII 200㎍, 첨가된 결핵균 200㎍으로 면역주사되었다. 생쥐들은 3주간 복막내 주사로 처리되었고 21 및 36일 사이에 매 3일마다 둘 중 하나의 중간치료를 복막내 주사로 매 3일마다 주입받았다: PBS 대조군, 3mg/kg IL-18bp-Fc, 및 3mg/kg IL-18bp-Fc-IL-1ra. 각 발에 대하여 CIA의 임상질병활성도가 두명의 실험조건을 모르는 숙련된 실험자에 의해 3점 등급을 이용하여 격일로 평가되었다. 데이터들은 치료그룹 vs 최초 콜라겐 주사 후 일수에 대한 임상질병활성도점수(평균±평균오차)로 표현되었다.
| 임상질병활성도점수 | |
| PBS 대조군 | 8.8±0.7 |
| IL-18bp-Fc | 6.5±0.6 |
| IL-18bp-Fc-IL-1ra | 3.8±0.5 |
실시예
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접촉 과민성(contact hypersensitive) 생쥐 모델에서의 IL-18bp-Fc-IL-1ra의 체내 실험이 수행되었다.
CHS의 유발 및 IL-18bp 키메라 치료
C57BL/6 생쥐들(생후 8 및 14주)이 사용되었다. DNFB, 아세톤, 에반스 블루, 포름아마이드, BSA, PMA, 이오노마이신(ionomycin), 브레펠딘(brefeldin), 및 LPS(Escherichia coli 026:B6)을 시그마-앨드리치사(세인트루이스, MO)로부터 구입하였다. DNFB는 사용 직전에 아세톤/올리브오일(4/1)로 희석되었다. 생쥐들은 0.5% DNFB용액 25㎕를 털을 민 등쪽 피부에 발라 감작하거나(sensitize) 그냥 두었다(대조). 5일 후 0.2% DNFB용액 10㎕를 우측귀의 양쪽면에 도포하고 동일양의 용매만을 좌측귀에 도포하였다. 시험도포 5일전부터 캘리퍼를 이용하여 귀의 두께를 날마다 조사하였다. 귀의 비후가 ((Tn-T5)우측귀 - (Tn-T5)좌측귀)에 따라 계산되었는데, 여기서 Tn 및 T5 는 n 일째 및 시험도포 5일 전날 관찰된 귀의 두께를 나타낸다. 관측된 비후가 비특이적인 자극이 아닌 DNFB-특이적인 염증에 의한 것임을 확인하기 위해 비감작되어 도포된 대조그룹이 각 실험에 포함되었다. IL-18 및/또는 IL-1들은 날마다 동물당 250㎕의 IL-18bp-Fc 또는 IL-18bp-Fc-IL-1ra의 복막내 주사에 의해 5일째에 시험도포 전에 60분을 개시하면서 중화되었다. 대조군 동물들은 운반체 식염수만을 주입받았다. 주된 재노출 도중의 치료는 7일에 중단되었다.
결과
IL-18bp-Fc-IL-1ra의 치료용 처치는 CHS를 예방하였음.
실험적으로 CHS를 유발하기 위해 생쥐들은 털을 민 등에 합텐(hapten)으로 감작되었다. 5일 후 귀에 DNFB를 도포함으로써 CHS가 유도되었다. 염증은 DNFB 도포된 비후의 증가 vs 용매만을 도포한 대조군 귀로서 채점되었다.
5-7일째 유도기 도중의 IL-18bp-Fc 및 IL-18bp-Fc-IL-1ra의 투여는 총 반응기간에 대하여 DNFB 도포된 귀의 비후를 현저히 감소시켰다(표 1). IL-18bp-Fc 및 IL-18bp-Fc-IL-1ra 사이의 현저한 상이점이 관찰되었는데(표 1), 이는 IL-1 및 IL-18 이중봉쇄가 동일지역에서 발생하거나, IL-18bp-Fc-IL-1ra의 IL-1 수용체 풍부 부위 지향 특성이 효과에 있어서 중요한 역할을 수행했다는 것 중 하나를 시사한다. IL-18bp-Fc-IL-1ra는 IL-18bp-Fc보다 현저히 우수하다.
표 4: 유도중 IL-18BP의 처리는 CHS를 예방하였음. C57BL/6 생쥐들은 0일에 DNFB로 감작되었고, 5일 후에 귀에 시험도포되었다. 귀 비후는 날마다 측정되었고 DNFB 도포된 비후의 증가 vs 용매만을 도포한 대조군 귀로서 표현되었다. 동물들은 IL-18bp 키메라 또는 운반체만으로 매일 처치되었다. 데이터들은 그룹당 5마리 생쥐의 평균이다.
| 일 | 5 | 6 | 7 |
| 처치 안함 | 0±0 | 110±12 | 160±10 |
| IL-18bp-Fc | 0±0 | 80±9 | 105±8 |
| IL-18BP-Fc-IL-1ra | 0±0 | 50±5 | 70±5 |
실시예
7
IL-1 수용체 결합 실험이 수행되었다.
간략히, 유전자 재조합 인간 IL-1 수용체 세포외영역이 최초로 발현되었고, 포유류 CHO 세포들을 이용하여 실내에서 정제되었다. TNFRII-Fc-IL-1ra, 음성 대조군 TNFRII-Fc 및 양성대조군 IL-1ra(키네레트)가 96 구멍판에 100㎕의 코팅 완충액(시그마) 내의 1㎍/구멍 코팅되었다. 정제된 IL-1 수용체(0.1㎍/구멍)이 이후 37℃의 PBS에서 45분간 배양되었다. 수용체/리간트 결합은 토끼 항 인간 IL-1 수용체 세포외영역 항체들(R&D 시스템) 및 이어서 HRP가 접합된 염소 항-토끼 IgG(피어스)로 검출되었다. PBS-T로 세척한 후, TMB(시그마, T8655)와 혼합함으로써 발색반응이 전개되었다. 판의 광학밀도(OD)가 650nm에서 EL800 만능 마이크로플레이트 판독기(바이오-텍) 내에서 읽혀졌다. OD 수치는 희석시간에 대하여 그래프로 작성되었다. 도 13은 TNFRII-Fc-IL-1ra 및IL-1ra(키네레트) 모두는 IL-1 수용체에 결합하고, TNFRII-Fc(엔브렐)는 그렇지 않음을 보여준다. 흥미롭게도, TNFRII-Fc-IL-1ra(포유류에서 제조)는 ㄸ-coli가 만든 IL-1ra(키네레트)보다 IL-1 수용체에 현저하게 우수하게 결합한다. 또한, 포유류가 만든 IL-1ra는 두개의 N-연결된 당화부위를 포함하며 따라서 혈청단백질 결합을 적게 가지고 체외결합특성에 있어서 E-coli가 만든 IL-1ra(키네레트)의 경우와 일관되게 상이하다.
실시예
8
TNFRII-Fc-IL-1ra, IL-4R-Fc-IL-1ra, 및 IL-18bp-Fc-IL-1ra뿐만 아니라 이들의 IL-1ra가 융합되지 않은 대조군들의 125-I 표지 및 동물실험이 수행되었다.
125-I 표지된 TNFRII-Fc-IL-1ra, IL-4R-Fc-IL-1ra, 및 IL-18bp-Fc-IL-1ra들은 인도젠(Indogen)법에 의해 제조되었고 크기배제 크로마토그래피에 의해 정제되었다(M 휴이 등, 1989). IL-1 수용체 결합 분석은 융합된 가내 포유류 유전자 재조합 IL- 수용체 세포외영역에 의해 확립되어있다(상기 실시예 4 참조). 125-I 표지된 TNFRII-Fc-IL-1ra에의 IL-1 수용체의 결합은 방사능표지되지않은 TNFRII-Fc-IL-1ra과 면면이 비교되었다. 실험결과는 125-I 표지된 TNFRII-Fc-IL-1ra가 IL-1 수용체 결합의 견지에서 기능적이라는 것을 나타낸다.
200㎕ 내의 6nmol의 TPA로 귀를 도포함으로써 처치된 생쥐들은 2-3일 내에 계속해서 피부염증이 발전하였다. 125-I 표지된 TNFRII-Fc-IL-1ra가 125-I 표지된 TNFRII-Fc(엔브렐)와 함께 피부-염증 생쥐모델에게 주사되었다. 놀랍게도, 실험결과는 125-I 표지된 TNFRII-Fc가 TNFRII-Fc보다 염증 부위에 더욱 공헌하였음을 나타내었다(표 1). 이는 IL-1 수용체 결합 친화도 때문인듯하다.
125-I 표지된 TNFRII-Fc-IL-1ra 및 IL-18bp-Fc-IL-1ra가 125-I 표지된 IL-4R-Fc 및 IL-18bp-Fc와 함께 피부-염증 생쥐모델에게 주사되었다. 유사한 결과가 얻어졌다(표 2 및 3).
표 5: 주입 4시간 후의 염증이 발생한 또는 발생하지 않은 조직 내의 125-I 표지된 TNFRII-Fc-IL-1ra 및 TNFRII-Fc(엔브렐) 분포. 본 분포는 조직의 그램당 주입된 양의 %로 표현되었다(n=6).
| 처치 | 조직 | 조직의 그램당 주입된 양의 % (n=6) |
| TNFRII-Fc-IL-1ra 125-I | 염증발생 피부 | 3.8±0.2 |
| TNFRII-Fc-IL-1ra 125-I | 정상피부 | 1.5±0.1 |
| TNFRII-Fc(엔브렐) 125-I | 염증발생 피부 | 2.8±0.2 |
| TNFRII-Fc(엔브렐) 125-I | 정상피부 | 1.4±0.2 |
표 6: 주입 4시간 후의 염증이 발생한 또는 발생하지 않은 조직 내의 125-I 표지된 IL-4R-Fc-IL-1ra 및 IL-4R-Fc 분포. 본 분포는 조직의 그램당 주입된 양의 %로 표현되었다(n=6).
| 처치 | 조직 | 조직의 그램당 주입된 양의 % (n=6) |
| TNFRII-Fc-IL-1ra 125-I | 염증발생 피부 | 4.0±0.2 |
| TNFRII-Fc-IL-1ra 125-I | 정상피부 | 1.6±0.1 |
| TNFRII-Fc(엔브렐) 125-I | 염증발생 피부 | 1.4±0.3 |
| TNFRII-Fc(엔브렐) 125-I | 정상피부 | 1.4±0.2 |
표 7: 주입 4시간 후의 염증이 발생한 또는 발생하지 않은 조직 내의 125-I 표지된 IL-18bp-Fc-IL-1ra 및 ILK-18bp-Fc 분포. 본 분포는 조직의 그램당 주입된 양의 %로 표현되었다(n=6).
| 처치 | 조직 | 조직의 그램당 주입된 양의 % (n=6) |
| TNFRII-Fc-IL-1ra 125-I | 염증발생 피부 | 3.9±0.3 |
| TNFRII-Fc-IL-1ra 125-I | 정상피부 | 1.4±0.5 |
| TNFRII-Fc(엔브렐) 125-I | 염증발생 피부 | 1.5±0.3 |
| TNFRII-Fc(엔브렐) 125-I | 정상피부 | 1.4±0.3 |
실시예
9
IL-4R-Fc-IL-1ra의 면역원성이 두마리의 필리핀 원숭이(cynomolgus monkey) 내에서 측정되었다. 주당 10mg의 IL-4R-Fc-IL-1ra이 8주간 주입되었다. 주사 전후(1일 및 56일)의 혈청 샘플이 채취되었다. 샘플들은 키메라 단백질의 IL-4 및 IL-1 생활성을 중화하는 항 키메라 IL-4R-Fc-IL-1 항체들의 존재에 대해 확립된 중화분석법에 의해 분석되었다. 낮은 농도의 중화 항체들을 추가로 검출하기 위하여, 혈청 샘플들은 단백질-A 및 항-인간 IgM 항체들에 의해 친화정제되었다. 희석되지 않은 혈청 및 정제된 IgG 및 IgM 모두에 의해 키메라 단백질의 IL-4 및 IL-1 생활성을 중화하는 항체들이 처치된 원숭이 내에서 발견되지 않았다. 실험결과는 키메라 IL-4R-Fc-IL-1ra는 원숭이 및 사람에게 면역원성이 아니라는 것을 시사한다.
본 명세서에 포함되어 있음.
SEQUENCE LISTING
<110> Hui, Mizhou
<120> CHIMERIC PROTEIN
<130> 08919-001001
<150> PCT/US2005/012194
<151> 2005-04-08
<150> US 60/618,476
<151> 2004-10-12
<150> US 60, 628,994
<151> 2004-11-17
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145 150 155 160
Gln Ile Cys Asn Val Val Ala Ile Pro Gly Asn Ala Ser Met Asp Ala
165 170 175
Val Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala Pro Gly Ala Val
180 185 190
His Leu Pro Gln Pro Val Ser Thr Arg Ser Gln His Thr Gln Pro Thr
195 200 205
Pro Glu Pro Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly
210 215 220
Pro Ser Pro Pro Ala Glu Gly Ser Thr Gly Asp Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe
465 470 475 480
Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln
485 490 495
Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Lys Glu Lys
500 505 510
Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His
515 520 525
Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg
530 535 540
Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys
545 550 555 560
Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr
565 570 575
Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met
580 585 590
Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val
595 600 605
Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
610 615
<210> 6
<211> 201
<212> PRT
<213> Homo sapiens
<400> 6
Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu
1 5 10 15
Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro
20 25 30
His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys
35 40 45
Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys
50 55 60
Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp
65 70 75 80
Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu
85 90 95
Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val
100 105 110
Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg
115 120 125
Lys Asn Gln Tyr Arg His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe
130 135 140
Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu
145 150 155 160
Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu
165 170 175
Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr
180 185 190
Lys Leu Cys Leu Pro Gln Ile Glu Asn
195 200
<210> 7
<211> 433
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 7
Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu
1 5 10 15
Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro
20 25 30
His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys
35 40 45
Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys
50 55 60
Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp
65 70 75 80
Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu
85 90 95
Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val
100 105 110
Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg
115 120 125
Lys Asn Gln Tyr Arg His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe
130 135 140
Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu
145 150 155 160
Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu
165 170 175
Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr
180 185 190
Lys Leu Cys Leu Pro Gln Ile Glu Asn Glu Pro Lys Ser Cys Asp Lys
195 200 205
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
210 215 220
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
225 230 235 240
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
245 250 255
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
260 265 270
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
275 280 285
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
290 295 300
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
305 310 315 320
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
325 330 335
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
340 345 350
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
355 360 365
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
370 375 380
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
385 390 395 400
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
405 410 415
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
420 425 430
Lys
<210> 8
<211> 585
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 8
Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu
1 5 10 15
Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro
20 25 30
His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys
35 40 45
Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys
50 55 60
Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp
65 70 75 80
Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu
85 90 95
Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val
100 105 110
Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg
115 120 125
Lys Asn Gln Tyr Arg His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe
130 135 140
Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu
145 150 155 160
Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu
165 170 175
Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr
180 185 190
Lys Leu Cys Leu Pro Gln Ile Glu Asn Glu Pro Lys Ser Cys Asp Lys
195 200 205
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
210 215 220
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
225 230 235 240
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
245 250 255
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
260 265 270
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
275 280 285
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
290 295 300
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
305 310 315 320
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
325 330 335
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
340 345 350
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
355 360 365
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
370 375 380
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
385 390 395 400
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
405 410 415
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
420 425 430
Lys Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
435 440 445
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
450 455 460
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Lys Glu Lys Ile Asp
465 470 475 480
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
485 490 495
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
500 505 510
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
515 520 525
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
530 535 540
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
545 550 555 560
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
565 570 575
Thr Lys Phe Tyr Phe Gln Glu Asp Glu
580 585
<210> 9
<211> 430
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
100 105 110
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
115 120 125
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
130 135 140
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
145 150 155 160
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
165 170 175
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
180 185 190
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
195 200 205
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
210 215 220
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
225 230 235 240
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
245 250 255
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
260 265 270
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
275 280 285
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
290 295 300
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
305 310 315 320
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
325 330 335
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
340 345 350
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
355 360 365
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
370 375 380
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
385 390 395 400
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
405 410 415
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
420 425 430
<210> 10
<211> 582
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
100 105 110
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
115 120 125
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
130 135 140
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
145 150 155 160
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
165 170 175
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
180 185 190
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
195 200 205
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
210 215 220
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
225 230 235 240
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
245 250 255
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
260 265 270
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
275 280 285
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
290 295 300
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
305 310 315 320
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
325 330 335
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
340 345 350
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
355 360 365
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
370 375 380
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
385 390 395 400
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
405 410 415
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Arg Pro
420 425 430
Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp Asp Val
435 440 445
Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly Tyr
450 455 460
Leu Gln Gly Pro Asn Val Asn Leu Lys Glu Lys Ile Asp Val Val Pro
465 470 475 480
Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys Met Cys
485 490 495
Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu Ala
500 505 510
Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg Phe
515 520 525
Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala
530 535 540
Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp Gln Pro
545 550 555 560
Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr Lys Phe
565 570 575
Tyr Phe Gln Glu Asp Glu
580
<210> 11
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 11
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 12
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 12
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Ile Phe Ser Asn His
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Ser Lys Ser Ile Asn Ser Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ala
65 70 75 80
Val Tyr Leu Gln Met Thr Asp Leu Arg Thr Glu Asp Thr Gly Val Tyr
85 90 95
Tyr Cys Ser Arg Asn Tyr Tyr Gly Ser Thr Tyr Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 13
<211> 601
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 13
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Ile Phe Ser Asn His
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Ser Lys Ser Ile Asn Ser Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ala
65 70 75 80
Val Tyr Leu Gln Met Thr Asp Leu Arg Thr Glu Asp Thr Gly Val Tyr
85 90 95
Tyr Cys Ser Arg Asn Tyr Tyr Gly Ser Thr Tyr Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
450 455 460
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
465 470 475 480
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Lys Glu Lys Ile Asp
485 490 495
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
500 505 510
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
515 520 525
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
530 535 540
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
545 550 555 560
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
565 570 575
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
580 585 590
Thr Lys Phe Tyr Phe Gln Glu Asp Glu
595 600
<210> 14
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 14
Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Phe Val Gly Ser Ser
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Met Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Thr Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Ser His Ser Trp Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Asn Leu Glu Val Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 15
<211> 192
<212> PRT
<213> Homo sapiens
<400> 15
Met Arg His Asn Trp Thr Pro Asp Leu Ser Pro Leu Trp Val Leu Leu
1 5 10 15
Leu Cys Ala His Val Val Thr Leu Leu Val Arg Ala Thr Pro Val Ser
20 25 30
Gln Thr Thr Thr Ala Ala Thr Ala Ser Val Arg Ser Thr Lys Asp Pro
35 40 45
Cys Pro Ser Gln Pro Pro Val Phe Pro Ala Ala Lys Gln Cys Pro Ala
50 55 60
Leu Glu Val Thr Trp Pro Glu Val Glu Val Pro Leu Asn Gly Thr Leu
65 70 75 80
Ser Leu Ser Cys Val Ala Cys Ser Arg Phe Pro Asn Phe Ser Ile Leu
85 90 95
Tyr Trp Leu Gly Asn Gly Ser Phe Ile Glu His Leu Pro Gly Arg Leu
100 105 110
Trp Glu Gly Ser Thr Ser Arg Glu Arg Gly Ser Thr Gly Thr Gln Leu
115 120 125
Cys Lys Ala Leu Val Leu Glu Gln Leu Thr Pro Ala Leu His Ser Thr
130 135 140
Asn Phe Ser Cys Val Leu Val Asp Pro Glu Gln Val Val Gln Arg His
145 150 155 160
Val Val Leu Ala Gln Leu Trp Ala Gly Leu Arg Ala Thr Leu Pro Pro
165 170 175
Thr Gln Glu Ala Leu Pro Ser Ser His Ser Ser Pro Gln Gln Gln Gly
180 185 190
<210> 16
<211> 424
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 16
Met Arg His Asn Trp Thr Pro Asp Leu Ser Pro Leu Trp Val Leu Leu
1 5 10 15
Leu Cys Ala His Val Val Thr Leu Leu Val Arg Ala Thr Pro Val Ser
20 25 30
Gln Thr Thr Thr Ala Ala Thr Ala Ser Val Arg Ser Thr Lys Asp Pro
35 40 45
Cys Pro Ser Gln Pro Pro Val Phe Pro Ala Ala Lys Gln Cys Pro Ala
50 55 60
Leu Glu Val Thr Trp Pro Glu Val Glu Val Pro Leu Asn Gly Thr Leu
65 70 75 80
Ser Leu Ser Cys Val Ala Cys Ser Arg Phe Pro Asn Phe Ser Ile Leu
85 90 95
Tyr Trp Leu Gly Asn Gly Ser Phe Ile Glu His Leu Pro Gly Arg Leu
100 105 110
Trp Glu Gly Ser Thr Ser Arg Glu Arg Gly Ser Thr Gly Thr Gln Leu
115 120 125
Cys Lys Ala Leu Val Leu Glu Gln Leu Thr Pro Ala Leu His Ser Thr
130 135 140
Asn Phe Ser Cys Val Leu Val Asp Pro Glu Gln Val Val Gln Arg His
145 150 155 160
Val Val Leu Ala Gln Leu Trp Ala Gly Leu Arg Ala Thr Leu Pro Pro
165 170 175
Thr Gln Glu Ala Leu Pro Ser Ser His Ser Ser Pro Gln Gln Gln Gly
180 185 190
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
195 200 205
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
210 215 220
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
225 230 235 240
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
245 250 255
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
260 265 270
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
275 280 285
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
290 295 300
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
305 310 315 320
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
325 330 335
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
340 345 350
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
355 360 365
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
370 375 380
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
385 390 395 400
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
405 410 415
Ser Leu Ser Leu Ser Pro Gly Lys
420
<210> 17
<211> 576
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 17
Met Arg His Asn Trp Thr Pro Asp Leu Ser Pro Leu Trp Val Leu Leu
1 5 10 15
Leu Cys Ala His Val Val Thr Leu Leu Val Arg Ala Thr Pro Val Ser
20 25 30
Gln Thr Thr Thr Ala Ala Thr Ala Ser Val Arg Ser Thr Lys Asp Pro
35 40 45
Cys Pro Ser Gln Pro Pro Val Phe Pro Ala Ala Lys Gln Cys Pro Ala
50 55 60
Leu Glu Val Thr Trp Pro Glu Val Glu Val Pro Leu Asn Gly Thr Leu
65 70 75 80
Ser Leu Ser Cys Val Ala Cys Ser Arg Phe Pro Asn Phe Ser Ile Leu
85 90 95
Tyr Trp Leu Gly Asn Gly Ser Phe Ile Glu His Leu Pro Gly Arg Leu
100 105 110
Trp Glu Gly Ser Thr Ser Arg Glu Arg Gly Ser Thr Gly Thr Gln Leu
115 120 125
Cys Lys Ala Leu Val Leu Glu Gln Leu Thr Pro Ala Leu His Ser Thr
130 135 140
Asn Phe Ser Cys Val Leu Val Asp Pro Glu Gln Val Val Gln Arg His
145 150 155 160
Val Val Leu Ala Gln Leu Trp Ala Gly Leu Arg Ala Thr Leu Pro Pro
165 170 175
Thr Gln Glu Ala Leu Pro Ser Ser His Ser Ser Pro Gln Gln Gln Gly
180 185 190
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
195 200 205
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
210 215 220
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
225 230 235 240
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
245 250 255
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
260 265 270
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
275 280 285
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
290 295 300
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
305 310 315 320
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
325 330 335
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
340 345 350
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
355 360 365
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
370 375 380
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
385 390 395 400
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
405 410 415
Ser Leu Ser Leu Ser Pro Gly Lys Arg Pro Ser Gly Arg Lys Ser Ser
420 425 430
Lys Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr
435 440 445
Leu Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val
450 455 460
Asn Leu Lys Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu
465 470 475 480
Phe Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser
485 490 495
Gly Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu
500 505 510
Ser Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp
515 520 525
Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe
530 535 540
Leu Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met
545 550 555 560
Pro Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
565 570 575
<210> 18
<211> 713
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 18
Met Asn Cys Arg Glu Leu Pro Leu Thr Leu Trp Val Leu Ile Ser Val
1 5 10 15
Ser Thr Ala Glu Ser Cys Thr Ser Arg Pro His Ile Thr Val Val Glu
20 25 30
Gly Glu Pro Phe Tyr Leu Lys His Cys Ser Cys Ser Leu Ala His Glu
35 40 45
Ile Glu Thr Thr Thr Lys Ser Trp Tyr Lys Ser Ser Gly Ser Gln Glu
50 55 60
His Val Glu Leu Asn Pro Arg Ser Ser Ser Arg Ile Ala Leu His Asp
65 70 75 80
Cys Val Leu Glu Phe Trp Pro Val Glu Leu Asn Asp Thr Gly Ser Tyr
85 90 95
Phe Phe Gln Met Lys Asn Tyr Thr Gln Lys Trp Lys Leu Asn Val Ile
100 105 110
Arg Arg Asn Lys His Ser Cys Phe Thr Glu Arg Gln Val Thr Ser Lys
115 120 125
Ile Val Glu Val Lys Lys Phe Phe Gln Ile Thr Cys Glu Asn Ser Tyr
130 135 140
Tyr Gln Thr Leu Val Asn Ser Thr Ser Leu Tyr Lys Asn Cys Lys Lys
145 150 155 160
Leu Leu Leu Glu Asn Asn Lys Asn Pro Thr Ile Lys Lys Asn Ala Glu
165 170 175
Phe Glu Asp Gln Gly Tyr Tyr Ser Cys Val His Phe Leu His His Asn
180 185 190
Gly Lys Leu Phe Asn Ile Thr Lys Thr Phe Asn Ile Thr Ile Val Glu
195 200 205
Asp Arg Ser Asn Ile Val Pro Val Leu Leu Gly Pro Lys Leu Asn His
210 215 220
Val Ala Val Glu Leu Gly Lys Asn Val Arg Leu Asn Cys Ser Ala Leu
225 230 235 240
Leu Asn Glu Glu Asp Val Ile Tyr Trp Met Phe Gly Glu Glu Asn Gly
245 250 255
Ser Asp Pro Asn Ile His Glu Glu Lys Glu Met Arg Ile Met Thr Pro
260 265 270
Glu Gly Lys Trp His Ala Ser Lys Val Leu Arg Ile Glu Asn Ile Gly
275 280 285
Glu Ser Asn Leu Asn Val Leu Tyr Asn Cys Thr Val Ala Ser Thr Gly
290 295 300
Gly Thr Asp Thr Lys Ser Phe Ile Leu Val Arg Lys Ala Asp Met Ala
305 310 315 320
Asp Ile Pro Gly His Val Phe Thr Arg Glu Pro Lys Ser Cys Asp Lys
325 330 335
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
340 345 350
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
355 360 365
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
370 375 380
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
385 390 395 400
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
405 410 415
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
420 425 430
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
435 440 445
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
450 455 460
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
465 470 475 480
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
485 490 495
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
500 505 510
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
515 520 525
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
530 535 540
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
545 550 555 560
Lys Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
565 570 575
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
580 585 590
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Lys Glu Lys Ile Asp
595 600 605
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
610 615 620
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
625 630 635 640
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
645 650 655
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
660 665 670
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
675 680 685
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
690 695 700
Thr Lys Phe Tyr Phe Gln Glu Asp Glu
705 710
<210> 19
<211> 232
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 19
Met Gly Trp Leu Cys Ser Gly Leu Leu Phe Pro Val Ser Cys Leu Val
1 5 10 15
Leu Leu Gln Val Ala Ser Ser Gly Asn Met Lys Val Leu Gln Glu Pro
20 25 30
Thr Cys Val Ser Asp Tyr Met Ser Ile Ser Thr Cys Glu Trp Lys Met
35 40 45
Asn Gly Pro Thr Asn Cys Ser Thr Glu Leu Arg Leu Leu Tyr Gln Leu
50 55 60
Val Phe Leu Leu Ser Glu Ala His Thr Cys Ile Pro Glu Asn Asn Gly
65 70 75 80
Gly Ala Gly Cys Val Cys His Leu Leu Met Asp Asp Val Val Ser Ala
85 90 95
Asp Asn Tyr Thr Leu Asp Leu Trp Ala Gly Gln Gln Leu Leu Trp Lys
100 105 110
Gly Ser Phe Lys Pro Ser Glu His Val Lys Pro Arg Ala Pro Gly Asn
115 120 125
Leu Thr Val His Thr Asn Val Ser Asp Thr Leu Leu Leu Thr Trp Ser
130 135 140
Asn Pro Tyr Pro Pro Asp Asn Tyr Leu Tyr Asn His Leu Thr Tyr Ala
145 150 155 160
Val Asn Ile Trp Ser Glu Asn Asp Pro Ala Asp Phe Arg Ile Tyr Asn
165 170 175
Val Thr Tyr Leu Glu Pro Ser Leu Arg Ile Ala Ala Ser Thr Leu Lys
180 185 190
Ser Gly Ile Ser Tyr Arg Ala Arg Val Arg Ala Trp Ala Gln Cys Tyr
195 200 205
Asn Thr Thr Trp Ser Glu Trp Ser Pro Ser Thr Lys Trp His Asn Ser
210 215 220
Tyr Arg Glu Pro Phe Glu Gln His
225 230
<210> 20
<211> 464
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 20
Met Gly Trp Leu Cys Ser Gly Leu Leu Phe Pro Val Ser Cys Leu Val
1 5 10 15
Leu Leu Gln Val Ala Ser Ser Gly Asn Met Lys Val Leu Gln Glu Pro
20 25 30
Thr Cys Val Ser Asp Tyr Met Ser Ile Ser Thr Cys Glu Trp Lys Met
35 40 45
Asn Gly Pro Thr Asn Cys Ser Thr Glu Leu Arg Leu Leu Tyr Gln Leu
50 55 60
Val Phe Leu Leu Ser Glu Ala His Thr Cys Ile Pro Glu Asn Asn Gly
65 70 75 80
Gly Ala Gly Cys Val Cys His Leu Leu Met Asp Asp Val Val Ser Ala
85 90 95
Asp Asn Tyr Thr Leu Asp Leu Trp Ala Gly Gln Gln Leu Leu Trp Lys
100 105 110
Gly Ser Phe Lys Pro Ser Glu His Val Lys Pro Arg Ala Pro Gly Asn
115 120 125
Leu Thr Val His Thr Asn Val Ser Asp Thr Leu Leu Leu Thr Trp Ser
130 135 140
Asn Pro Tyr Pro Pro Asp Asn Tyr Leu Tyr Asn His Leu Thr Tyr Ala
145 150 155 160
Val Asn Ile Trp Ser Glu Asn Asp Pro Ala Asp Phe Arg Ile Tyr Asn
165 170 175
Val Thr Tyr Leu Glu Pro Ser Leu Arg Ile Ala Ala Ser Thr Leu Lys
180 185 190
Ser Gly Ile Ser Tyr Arg Ala Arg Val Arg Ala Trp Ala Gln Cys Tyr
195 200 205
Asn Thr Thr Trp Ser Glu Trp Ser Pro Ser Thr Lys Trp His Asn Ser
210 215 220
Tyr Arg Glu Pro Phe Glu Gln His Glu Pro Lys Ser Cys Asp Lys Thr
225 230 235 240
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
245 250 255
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
260 265 270
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
275 280 285
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
290 295 300
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
305 310 315 320
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
325 330 335
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
340 345 350
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
355 360 365
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
370 375 380
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
385 390 395 400
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
405 410 415
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
420 425 430
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
435 440 445
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 21
<211> 615
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 21
Met Gly Trp Leu Cys Ser Gly Leu Leu Phe Pro Val Ser Cys Leu Val
1 5 10 15
Leu Leu Gln Val Ala Ser Ser Gly Asn Met Lys Val Leu Gln Glu Pro
20 25 30
Thr Cys Val Ser Asp Tyr Met Ser Ile Ser Thr Cys Glu Trp Lys Met
35 40 45
Asn Gly Pro Thr Asn Cys Ser Thr Glu Leu Arg Leu Leu Tyr Gln Leu
50 55 60
Val Phe Leu Leu Ser Glu Ala His Thr Cys Ile Pro Glu Asn Asn Gly
65 70 75 80
Gly Ala Gly Cys Val Cys His Leu Leu Met Asp Asp Val Val Ser Ala
85 90 95
Asp Asn Tyr Thr Leu Asp Leu Trp Ala Gly Gln Gln Leu Leu Trp Lys
100 105 110
Gly Ser Phe Lys Pro Ser Glu His Val Lys Pro Arg Ala Pro Gly Asn
115 120 125
Leu Thr Val His Thr Asn Val Ser Asp Thr Leu Leu Leu Thr Trp Ser
130 135 140
Asn Pro Tyr Pro Pro Asp Asn Tyr Leu Tyr Asn His Leu Thr Tyr Ala
145 150 155 160
Val Asn Ile Trp Ser Glu Asn Asp Pro Ala Asp Phe Arg Ile Tyr Asn
165 170 175
Val Thr Tyr Leu Glu Pro Ser Leu Arg Ile Ala Ala Ser Thr Leu Lys
180 185 190
Ser Gly Ile Ser Tyr Arg Ala Arg Val Arg Ala Trp Ala Gln Cys Tyr
195 200 205
Asn Thr Thr Trp Ser Glu Trp Ser Pro Ser Thr Lys Trp His Asn Ser
210 215 220
Tyr Arg Glu Pro Phe Glu Gln His Glu Pro Lys Ser Cys Asp Lys Thr
225 230 235 240
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
245 250 255
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
260 265 270
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
275 280 285
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
290 295 300
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
305 310 315 320
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
325 330 335
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
340 345 350
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
355 360 365
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
370 375 380
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
385 390 395 400
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
405 410 415
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
420 425 430
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
435 440 445
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
465 470 475 480
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
485 490 495
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Lys Glu Lys Ile Asp Val
500 505 510
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
515 520 525
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
530 535 540
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
545 550 555 560
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
565 570 575
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
580 585 590
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
595 600 605
Lys Phe Tyr Phe Gln Glu Asp
610 615
<210> 22
<211> 856
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 22
Met Asp Ser Leu Ala Ser Leu Val Leu Cys Gly Val Ser Leu Leu Leu
1 5 10 15
Ser Gly Thr Val Glu Gly Ala Met Asp Leu Ile Leu Ile Asn Ser Leu
20 25 30
Pro Leu Val Ser Asp Ala Glu Thr Ser Leu Thr Cys Ile Ala Ser Gly
35 40 45
Trp Arg Pro His Glu Pro Ile Thr Ile Gly Arg Asp Phe Glu Ala Leu
50 55 60
Met Asn Gln His Gln Asp Pro Leu Glu Val Thr Gln Asp Val Thr Arg
65 70 75 80
Glu Trp Ala Lys Lys Val Val Trp Lys Arg Glu Lys Ala Ser Lys Ile
85 90 95
Asn Gly Ala Tyr Phe Cys Glu Gly Arg Val Arg Gly Glu Ala Ile Arg
100 105 110
Ile Arg Thr Met Lys Met Arg Gln Gln Ala Ser Phe Leu Pro Ala Thr
115 120 125
Leu Thr Met Thr Val Asp Lys Gly Asp Asn Val Asn Ile Ser Phe Lys
130 135 140
Lys Val Leu Ile Lys Glu Glu Asp Ala Val Ile Tyr Lys Asn Gly Ser
145 150 155 160
Phe Ile His Ser Val Pro Arg His Glu Val Pro Asp Ile Leu Glu Val
165 170 175
His Leu Pro His Ala Gln Pro Gln Asp Ala Gly Val Tyr Ser Ala Arg
180 185 190
Tyr Ile Gly Gly Asn Leu Phe Thr Ser Ala Phe Thr Arg Leu Ile Val
195 200 205
Arg Arg Cys Glu Ala Gln Lys Trp Gly Pro Glu Cys Asn His Leu Cys
210 215 220
Thr Ala Cys Met Asn Asn Gly Val Cys His Glu Asp Thr Gly Glu Cys
225 230 235 240
Ile Cys Pro Pro Gly Phe Met Gly Arg Thr Cys Glu Lys Ala Cys Glu
245 250 255
Leu His Thr Phe Gly Arg Thr Cys Lys Glu Arg Cys Ser Gly Gln Glu
260 265 270
Gly Cys Lys Ser Tyr Val Phe Cys Leu Pro Asp Pro Tyr Gly Cys Ser
275 280 285
Cys Ala Thr Gly Trp Lys Gly Leu Gln Cys Asn Glu Ala Cys His Pro
290 295 300
Gly Phe Tyr Gly Pro Asp Cys Lys Leu Arg Cys Ser Cys Asn Asn Gly
305 310 315 320
Glu Met Cys Asp Arg Phe Gln Gly Cys Leu Cys Ser Pro Gly Trp Gln
325 330 335
Gly Leu Gln Cys Glu Arg Glu Gly Ile Pro Arg Met Thr Pro Lys Ile
340 345 350
Val Asp Leu Pro Asp His Ile Glu Val Asn Ser Gly Lys Phe Asn Pro
355 360 365
Ile Cys Lys Ala Ser Gly Trp Pro Leu Pro Thr Asn Glu Glu Met Thr
370 375 380
Leu Val Lys Pro Asp Gly Thr Val Leu His Pro Lys Asp Phe Asn His
385 390 395 400
Thr Asp His Phe Ser Val Ala Ile Phe Thr Ile His Arg Ile Leu Pro
405 410 415
Pro Asp Ser Gly Val Trp Val Cys Ser Val Asn Thr Val Ala Gly Met
420 425 430
Val Glu Lys Pro Phe Asn Ile Ser Val Lys Val Leu Pro Lys Pro Leu
435 440 445
Asn Ala Pro Asn Val Ile Asp Thr Gly His Asn Phe Ala Val Ile Asn
450 455 460
Ile Ser Ser Glu Pro Tyr Phe Gly Glu Pro Lys Ser Cys Asp Lys Thr
465 470 475 480
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
485 490 495
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
500 505 510
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
515 520 525
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
530 535 540
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
545 550 555 560
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
565 570 575
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
580 585 590
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
595 600 605
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
610 615 620
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
625 630 635 640
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
645 650 655
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
660 665 670
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
675 680 685
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
690 695 700
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
705 710 715 720
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
725 730 735
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Lys Glu Lys Ile Asp Val
740 745 750
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
755 760 765
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
770 775 780
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
785 790 795 800
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
805 810 815
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
820 825 830
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
835 840 845
Lys Phe Tyr Phe Gln Glu Asp Glu
850 855
<210> 23
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 23
Asp Ile Gln Leu Ile Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
1 5 10 15
Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn
20 25 30
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu
35 40 45
Ile Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 24
<211> 718
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 24
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pro
20 25 30
Glu Leu Ser Leu Lys Gly Thr Gln His Ile Met Gln Ala Gly Gln Thr
35 40 45
Leu His Leu Gln Cys Arg Gly Glu Ala Ala His Lys Trp Ser Leu Pro
50 55 60
Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser Ile Thr Lys Ser Ala
65 70 75 80
Cys Gly Arg Asn Gly Lys Gln Phe Cys Ser Thr Leu Thr Leu Asn Thr
85 90 95
Ala Gln Ala Asn His Thr Gly Phe Tyr Ser Cys Lys Tyr Leu Ala Val
100 105 110
Pro Thr Ser Lys Lys Lys Glu Thr Glu Ser Ala Ile Tyr Ile Phe Ile
115 120 125
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
130 135 140
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
145 150 155 160
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
165 170 175
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
180 185 190
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
195 200 205
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
210 215 220
Gln Thr Asn Thr Ile Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val
225 230 235 240
Lys Leu Leu Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr
245 250 255
Pro Leu Asn Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys
260 265 270
Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His
275 280 285
Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys
290 295 300
Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys
305 310 315 320
Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys Ala Phe Ile Glu Pro
325 330 335
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
340 345 350
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
355 360 365
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
370 375 380
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
385 390 395 400
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
405 410 415
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
420 425 430
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
435 440 445
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
450 455 460
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
465 470 475 480
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
485 490 495
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
500 505 510
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
515 520 525
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
530 535 540
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
545 550 555 560
Ser Leu Ser Pro Gly Lys Arg Pro Ser Gly Arg Lys Ser Ser Lys Met
565 570 575
Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg
580 585 590
Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu
595 600 605
Lys Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu
610 615 620
Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp
625 630 635 640
Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu
645 650 655
Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly
660 665 670
Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys
675 680 685
Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp
690 695 700
Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
705 710 715
<210> 25
<211> 605
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetically generated peptide
<400> 25
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Tyr Pro Tyr Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln
450 455 460
Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn
465 470 475 480
Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Lys
485 490 495
Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly
500 505 510
Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu
515 520 525
Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn
530 535 540
Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro
545 550 555 560
Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr
565 570 575
Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu
580 585 590
Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
595 600 605
Claims (32)
- 융합 단백질의 아미노 말단에 위치하고 제1사이토카인 또는 성장인자와 특이적으로 결합하여 중화시키는 제1구역; 및융합 단백질의 카복실 말단에 위치하고 염증부위 또는 질병부위에 풍부한 제2사이토카인 수용체 또는 성장인자와 특이적으로 결합하는 제2구역을 포함하며,영역들은 수술적으로 연결되는 융합 단백질.
- 제 1항에 있어서,이합체화할 수 있으며 제1구역 및 제2구역을 연결하는 연결구역을 더욱 포함하는 융합 단백질.
- 제 2항에 있어서,상기 연결구역이 면역 글로불린 또는 이와 기능상 동등한 것의 Fc 분절을 포함하는 융합 단백질.
- 제 3항에 있어서,상기 면역글로불린이 IgA, IgE, IgD, IgG, 또는 IgM인 융합 단백질.
- 제 4항에 있어서,상기 면역글로불린이 IgG인 융합 단백질.
- 제 5항에 있어서,상기 Fc 분절이 SEQ ID NO.: 2를 포함하는 융합 단백질.
- 제 1항에 있어서,상기 제1구역이 VEGF, Ang, TNF, IL18, IL4 또는 IL13, 또는 이와 기능상 동등한 것에 결합하여 중화시키는 융합 단백질.
- 제 7항에 있어서,상기 제1구역이 VEGF, 안지오포이틴, TNF, IL18, IL4 또는 IL13, 또는 이와 기능상 동등한 것에 특이적으로 결합하여 중화시키는 면역글로불린의 사슬의 시퀀스를 포함하는 융합 단백질.
- 제 8항에 있어서,상기 면역글로불린 사슬이 SEQ ID NO.: 9, 11, 12, 14, 23 또는 24; 또는 이와 기능상 동등한 것을 포함하는 융합 단백질.
- 제 7항에 있어서,상기 제1구역이 VEGF, Ang, TNF, IL18, IL4 또는 IL13의 수용체 또는 결합 단백질의 시퀀스를 포함하는 융합 단백질.
- 제 10항에 있어서,상기 제1구역이 SEQ ID NO.: 3, 6, 15 또는 19를 포함하는 융합 단백질.
- 제 1항에 있어서,상기 단백질이 당화되는 융합 단백질.
- 제 1항에 있어서,상기 제2사이토카인이 IL-1인 융합 단백질.
- 제 13항에 있어서,상기 제2구역이 IL-1의 길항제인 융합 단백질.
- 제 14항에 있어서,상기 제2구역이 IL-1ra(SEQ ID NO.: 1) 또는 이와 기능상 동등한 유사물의 시퀀스를 포함하는 융합 단백질.
- 제 14항에 있어서,상기 단백질들이 SEQ ID NO.: 5, 8, 10, 13, 17, 18, 21, 22, 24 또는 25를 포함하는 융합 단백질.
- 제 1항의 융합 단백질을 암호화(encode)하는 시퀀스를 포함하는 분리된 핵산.
- 제 17항에 있어서,상기 핵산이 SEQ ID NO.: 1-25 중 하나를 암호화하는 시퀀스를 포함하는 핵산.
- 제 17항의 핵산을 포함하는 벡터.
- 제 17항의 핵산을 포함하는 숙주세포.
- 핵산에 의해 암호화된 폴리펩타이드의 발현을 용인하는 조건 하의 배지 내에서 제 20항의 숙주세포를 배양하는 단계, 및 배양된 세포 또는 세포의 배지로부터 폴리펩타이드를 정제하는 단계를 포함하는 폴리펩타이드의 제조방법.
- 제 1항의 융합 단백질 또는 융합 단백질을 암호화하는 핵산; 및 약학적으로 수용가능한 담체를 포함하는 조성물.
- 과도한 면역반응으로 특징지어지는 질환을 가지고 있거나 얻을 위험이 있는 대상을 분별하는 단계; 및상기 대상에 제 1항의 융합 단백질 또는 융합 단백질을 암호화하는 핵산의 유효량을 투여하는 단계를 포함하는 대상 내의 면역반응을 조절하는 방법.
- 제 23항에 있어서,상기 대상이 이종 또는 동종의 이식을 받았거나 받을 것으로 고려되는 방법.
- 제 23항에 있어서,상기 질환이 염증성 질병, 자가면역 질병, 알레르기성 질병, 또는 혈관생성 의존성 암인 방법.
- 제 25항에 있어서,상기 질환이 암이고, 융합 단백질이 SEQ ID NO.: 22, 24 및 25를 포함하는 방법.
- 융합 단백질 키메라를 형성하기 위해 SEQ ID NO.: 1 또는 이와 기능상 동등한 것을 포함하는 구역에 사이토카인 또는 성장인자에 결합하여 중화시키는 유전자 재조합 단백질을 가하는 단계; 및대상 내에서 유전자 단백질의 반감기를 측정하는 단계를 포함하는 대상 내의 유전자 재조합 단백질의 반감기를 증가시키는 방법.
- 융합 단백질 키메라를 형성하기 위해 SEQ ID NO.: 1 또는 이와 기능상 동등한 것을 포함하는 구역에 유전자 재조합 단백질을 가하는 단계; 및대상 내에서 융합 단백질의 효능을 측정하는 단계를 포함하는 대상 내의 유전자 재조합 단백질의 효능을 증가시키는 방법.
- 융합 단백질 키메라를 형성하기 위해 SEQ ID NO.: 1 또는 이와 기능상 동등한 것을 포함하는 구역에 IL-1 수용체가 풍부한 염증부위로 지향되는 치료용 단백질을 가하는 단계; 및필요로 하는 대상에게 융합 단백질 키메라를 투여하는 단계를 포함하는 대상 내의 목표에 치료용 단백질을 전달하는 방법.
- 제 28항에 있어서,상기 SEQ ID NO.: 1 또는 이와 기능상 동등한 것을 포함하는 구역이 IL-1 수용체에 결합하고, 유전자 재조합 단백질은 사이토카인 또는 성장인자에 결합하여 중화시키는 치료용 단백질인 방법.
- 제 30항에 있어서,상기 융합 단백질 키메라가 대상 내의 염증부위 또는 IL-1 수용체가 풍부한 질병부위에서 IL-1 수용체 및 사이토카인 또는 성장인자 양자에 결합하여 동시에 중화시키는 방법.
- 제 30항에 있어서,상기 융합 단백질 키메라가 대상 내의 염증부위 또는 IL-1 수용체가 풍부한 질병부위에서 IL-1 수용체 및 사이토카인 또는 성장인자 양자의 활성을 중화시키거나 대항하는 방법.
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| US61847604P | 2004-10-12 | 2004-10-12 | |
| US60/618,476 | 2004-10-12 | ||
| US62899404P | 2004-11-17 | 2004-11-17 | |
| US60/628,994 | 2004-11-17 | ||
| US65073405P | 2005-02-01 | 2005-02-01 |
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| EP (1) | EP1799246A4 (ko) |
| JP (1) | JP2008515970A (ko) |
| KR (1) | KR20080022539A (ko) |
| AU (1) | AU2005296277A1 (ko) |
| BR (1) | BRPI0516350A (ko) |
| CA (1) | CA2583937A1 (ko) |
| IL (1) | IL182497A0 (ko) |
| NZ (1) | NZ554481A (ko) |
| WO (1) | WO2006043972A1 (ko) |
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| US10259860B2 (en) | 2007-02-27 | 2019-04-16 | Aprogen Inc. | Fusion proteins binding to VEGF and angiopoietin |
| EP3825329A1 (en) * | 2007-12-26 | 2021-05-26 | Xencor, Inc. | Fc variants with altered binding to fcrn |
| EP2259774B1 (en) | 2008-02-27 | 2012-12-12 | Biomet Biologics, LLC | Methods and compositions for delivering interleukin-1 receptor antagonist |
| US8753690B2 (en) | 2008-02-27 | 2014-06-17 | Biomet Biologics, Llc | Methods and compositions for delivering interleukin-1 receptor antagonist |
| WO2009149205A2 (en) * | 2008-06-03 | 2009-12-10 | Neurotech Usa, Inc. | Cell lines that secrete soluble vegf receptors and uses thereof |
| CN102203258A (zh) * | 2008-07-02 | 2011-09-28 | 新兴产品开发西雅图有限公司 | TGF-β拮抗剂多靶点结合蛋白 |
| CA2729749A1 (en) * | 2008-07-02 | 2010-01-07 | Emergent Product Development Seattle, Llc | Tnf-a antagonist multi-target binding proteins |
| RU2595379C2 (ru) | 2009-04-16 | 2016-08-27 | АббВай Биотерапеутикс Инк. | АНТИТЕЛА ПРОТИВ TNF-α И ИХ ПРИМЕНЕНИЯ |
| AU2010262836B2 (en) | 2009-06-17 | 2015-05-28 | Abbvie Biotherapeutics Inc. | Anti-VEGF antibodies and their uses |
| EP2470162B1 (en) | 2009-08-27 | 2019-03-27 | Biomet Biologics, LLC | Implantable device for production of interleukin-1 receptor antagonist |
| KR101004363B1 (ko) * | 2010-03-19 | 2010-12-28 | 가톨릭대학교 산학협력단 | 자가 면역 질환 예방 및 치료용 ＴＮＦ－α와 ＩＬ－２１ 이중 길항제 |
| KR101004362B1 (ko) | 2010-03-19 | 2010-12-28 | 가톨릭대학교 산학협력단 | 자가 면역 질환 예방 및 치료용 ＴＮＦ－α와 ＴＷＥＡＫ 이중 길항제 |
| US20140154255A1 (en) | 2012-11-30 | 2014-06-05 | Abbvie Biotherapeutics Inc. | Anti-vegf antibodies and their uses |
| US9895418B2 (en) | 2013-03-15 | 2018-02-20 | Biomet Biologics, Llc | Treatment of peripheral vascular disease using protein solutions |
| US10143725B2 (en) | 2013-03-15 | 2018-12-04 | Biomet Biologics, Llc | Treatment of pain using protein solutions |
| US9878011B2 (en) * | 2013-03-15 | 2018-01-30 | Biomet Biologics, Llc | Treatment of inflammatory respiratory disease using biological solutions |
| US9758806B2 (en) | 2013-03-15 | 2017-09-12 | Biomet Biologics, Llc | Acellular compositions for treating inflammatory disorders |
| US20140271589A1 (en) | 2013-03-15 | 2014-09-18 | Biomet Biologics, Llc | Treatment of collagen defects using protein solutions |
| US10208095B2 (en) | 2013-03-15 | 2019-02-19 | Biomet Manufacturing, Llc | Methods for making cytokine compositions from tissues using non-centrifugal methods |
| US9950035B2 (en) | 2013-03-15 | 2018-04-24 | Biomet Biologics, Llc | Methods and non-immunogenic compositions for treating inflammatory disorders |
| EP3074507B1 (en) | 2013-11-26 | 2022-01-05 | Biomet Biologics, LLC | Methods of mediating macrophage phenotypes |
| US10441635B2 (en) | 2014-11-10 | 2019-10-15 | Biomet Biologics, Llc | Methods of treating pain using protein solutions |
| US9763800B2 (en) | 2015-03-18 | 2017-09-19 | Biomet C. V. | Implant configured for hammertoe and small bone fixation |
| CA3171969A1 (en) | 2020-05-25 | 2021-12-02 | Beijing Vdjbio Co., Ltd. | An interleukin-1 receptor antagonist and a fusion protein containing the same |
| CN113402583B (zh) * | 2021-06-19 | 2023-03-21 | 江西农业大学 | Qgk三肽及其应用 |
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| US6541610B1 (en) * | 1989-09-05 | 2003-04-01 | Immunex Corporation | Fusion proteins comprising tumor necrosis factor receptor |
| GEP20033082B (en) * | 1991-03-15 | 2003-10-27 | Amgen Inc | Pegylation of Polypeptides |
| US6548634B1 (en) * | 1998-09-30 | 2003-04-15 | Chiron Corporation | Synthetic peptides having FGF receptor affinity |
| EP1781684A4 (en) * | 2004-08-25 | 2008-05-21 | Amprotein Corp | NEW CHIMERE POLYPEPTIDE AND USE THEREOF |
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2005
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- 2005-04-08 JP JP2007536675A patent/JP2008515970A/ja active Pending
- 2005-04-08 CA CA002583937A patent/CA2583937A1/en not_active Abandoned
- 2005-04-08 WO PCT/US2005/012194 patent/WO2006043972A1/en active Application Filing
- 2005-04-08 KR KR1020077008321A patent/KR20080022539A/ko not_active Application Discontinuation
- 2005-04-08 AU AU2005296277A patent/AU2005296277A1/en not_active Abandoned
- 2005-04-08 NZ NZ554481A patent/NZ554481A/en unknown
- 2005-04-08 BR BRPI0516350-1A patent/BRPI0516350A/pt not_active IP Right Cessation
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2007
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Also Published As
| Publication number | Publication date |
|---|---|
| EP1799246A4 (en) | 2009-08-12 |
| BRPI0516350A (pt) | 2008-09-02 |
| WO2006043972A1 (en) | 2006-04-27 |
| EP1799246A1 (en) | 2007-06-27 |
| IL182497A0 (en) | 2007-09-20 |
| AU2005296277A1 (en) | 2006-04-27 |
| WO2006043972A8 (en) | 2006-06-15 |
| JP2008515970A (ja) | 2008-05-15 |
| NZ554481A (en) | 2010-04-30 |
| CA2583937A1 (en) | 2006-04-27 |
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